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Neurons and Muscles
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Neurons and Muscles
A. Malcolm Campbell, PhD

Christopher J. Paradise, PhD
Neurons and Muscles

Copyright © A. Malcolm Campbell and Christopher J. Paradise. 2016.
All rights reserved. No part of this publication may be reproduced, stored

in a retrieval system, or transmitted in any form or by any means—
electronic, mechanical, photocopy, recording, or any other except for
brief quotations, not to exceed 250 words, without the prior permission
of the publisher.
First published in 2016 by

Momentum Press®, LLC
222 East 46th Street, New York, NY 10017
www.momentumpress.net
ISBN-13: 978-1-94474-908-8 (print)

ISBN-13: 978-1-94474-907-1 (e-book)
Momentum Press Biology Collection
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Abstract
Whenever a dancer or an athlete performs amazing feats, it is the con-
sequence of two very interesting cell types: neurons and muscles. When
the two of these cell types work together, animals can move in complex
ways with surprising control. Not only do they work together to pro-
duce movement, they have many traits in common. They both convert
chemical signals into electrical information, and then back into chemical
information again. This book will examine how neurons process informa-
tion and communicate to adjacent cells. This book presents how muscle
cells know when to contract and how contraction leads to bigger muscles.
Finally, the last chapter presents how long-term memories are formed. In
all three chapters, some of the original data that have contributed to our
understanding of these two fascinating cell types are reproduced to pro-
vide supporting evidence for the function of these two cell types.
Keywords
allosterically modulated, transmembrane, covalent modulation, ligand-
gated, ion channels, depolarized, voltage-gated, refractory period, patch
clamp, myelin, nodes of Ranvier, secretory vesicles, skeletal muscle, motor
neurons, acetylcholine, sarcomere, striated, longitudinal sections, cross
sections, actin, myosin, troponin, tropomyosin, T-tubules, hypertrophy,
hyperplasia, performance-enhancing drugs, short-term memory, long-
term memory, sensory neurons, synapse, cAMP, PKA, MAPK
Contents
Preface...................................................................................................ix
Acknowledgments....................................................................................xi
Introduction.........................................................................................xiii
Chapter 1 Neurons Receive and Send Information.............................1
Chapter 2 Muscles Contract and Grow Bigger..................................21
Ethical, Legal, and Social Implications: Use of
Performance Enhancing Drugs.....................................29
Chapter 3 Memories Require New Proteins in Neurons....................33
Ethical, Legal, and Social Implications: Concerns
About Memory Research..............................................41
Conclusion............................................................................................45
Glossary................................................................................................47
Index....................................................................................................49
Preface
This book about neurons and muscles is part of a thirty book series that
collectively surveys all of the major themes in biology. Rather than just
present information as a collection of facts, the reader is treated more like
a scientist, which means the data behind the major themes are presented.
Reading any of the thirty books by Campbell and Paradise provides read-
ers with biological context and comprehensive perspective so that readers
can learn important information from a single book with the potential to
see how the major themes span all size scales: molecular, cellular, organ-
ismal, population and ecologic systems. The major themes of biology en-
capsulate the entire discipline: information, evolution, cells, homeostasis
and emergent properties.
In the twentieth century, biology was taught with a heavy emphasis
on long lists of terms and many specific details. All of these details were
presented in a way that obscured a more comprehensive understanding.
In this book, readers will learn how neurons and muscles work and some
of the supporting evidence behind our understanding. Instead of believ-
ing or simply accepting information, readers of this book will learn about
the science behind the production of proteins the way professional scien-
tists do—with experimentation and data analysis. In short, data are put
back into the teaching of biological sciences.
Readers of this book who wish to see the textbook version of this
content can go to www.bio.davidson.edu/icb where they will find
pedagogically-designed and interactive Integrating Concepts in Biology for
introductory biology college courses or a high school AP Biology course.
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Acknowledgments
Publishing this book would not have been possible without the generous
gift of Dr. David Botstein who shared some of his Breakthrough Prize
with AMC. David’s gift allowed us to hire talented artists (Tom Webster
and his staff at Lineworks, Inc.) and copyeditor Laura Loveall. Thanks go
to Kristen Mandava for project management and guidance on the pub-
lishing process. In particular, we are indebted to Katie Noble and Melissa
Hayban for their many hours of help and attention to detail.
Kristen Eshleman, Paul Brantley, Bill Hatfield and Olivia Booker
helped us with technology at Davidson College. We are grateful to ad-
ministrators Tom Ross, Clark Ross, Carol Quillen, Wendy Raymond,
Verna Case, and Barbara Lom who had confidence in us and encouraged
us to persist despite setbacks along the way.
These books were the product of the shared labor of my two vision-
ary coauthors Laurie Heyer and Chris Paradise. We shared the dream
and the hardships and developed this book from scratch. My family has
been very supportive and I thank Susan, Celeste and Paulina for their
support and patience. I also want to thank Jan Serie, my pedagogical
mentor, who taught me so much about the art and science of helping stu-
dents learn. I benefited from the support of the Howard Hughes Medi-
cal Institute grant 52006292, the James G. Martin Genomics Program,
and Davidson College. This book would not have survived its first draft
without my students who endured the typos and the early versions of this
book. These undergraduates participated in a bold experiment to see if
beginners could construct their own knowledge, retain what they learned,
and transform the way they see themselves and the discipline of biology.
While many people said that beginning students were not up to the task,
my students proved them wrong.
Introduction
This book focuses on neurons and muscles. In many ways, cells are similar
to computers. Cells and computers both work from a set of directions and
respond to inputs. Both store information, come in a variety of shapes,
consume energy, use electricity to function, and both can be infected by
viruses. Over time, humans have engineered smaller and smaller comput-
ers to the point that cells have been built to function as computers. The
next generation of computers will include human cells that have been
programmed with DNA and can be implanted into humans to aug-
ment our current functions. This chapter looks at two major functions
of neurons—communication to another cell and memory formation.
A muscle contracts when it receives the appropriate signal from a neuron.
Neurons can communicate information over long distances very quickly.
Muscles process the output from a neuron and convert that informa-
tion into a contraction that can lead to larger muscles. Neurons encode
memory by depositing new proteins that alter the cell’s function to benefit
the organism.
CHAPTER 1
Neurons Receive and Send

Information
At birth, all newborns know how to move their muscles (Figure 1). They
kick, scream, and nurse instinctively. Although they can move their mus-
cles from the first minute of life, they do not have to consciously think
about the cellular actions required to move their muscles. All they have
to do is tell their body to respond, and it does. How fast can nerve cells
work? In the blink of an eye. The desire to blink tells the muscles that
control the eyelids to contract and relax in a matter of milliseconds. Since
diffusion alone is too slow to transmit the “blink” command from the
brain to the eyelid muscles, cells must use a different mechanism for com-
munication. The desire to blink starts as a chemical signal that stimulates
a nerve which extends to the eyelid muscles. The neuron, or nerve cell,
receives the chemical input and converts the signal to an electrical cur-
rent that races down the axon to its terminal adjacent to the muscle cell.
At the neuromuscular junction, the neuron converts the electrical signal
back into a chemical message that is transmitted a very short distance
to the muscle, which interprets the information and contracts. The pro-
duction of cellular electricity begins with a modified version of signal
transduction.
Before understanding the neuron’s signal transduction, consider the
resting state of a neuron (Table 1). Cells do not maintain equal con-
centrations of ions inside and out. Because ions are charged particles,
they cannot pass through phospholipid bilayer membranes unassisted. In
most animal cells, more sodium ions (Na+) are excluded from the cyto-
plasm and accumulate in the extracellular environment. Conversely, cells
sequester more potassium ions (K+) in their cytoplasm than are typically
found outside the cells. Cells expend an enormous amount of energy to
2 NEURONS AND MUSCLES
Figure 1 Neurons use chemical and electrical signals to communicate

information. Neurons receive chemical inputs and convert them to
electrical signals that quickly convert the information to chemical
outputs. Chemical information is indicated by boxes and atomic
symbols; lightning bolts symbolize e lectrical signals.
Source: Original art.
maintain this unbalanced ionic state with a higher concentration of Na+

outside and a higher concentration of K+ inside.
Every cell on the planet has to regulate ions in order to live. Every
animal cell has in its plasma membrane Na+/K+ pumps to help regulate
sodium and potassium ions (Figure 2). As the name implies, a pump
is an active transporter, meaning that it requires energy in the form of
adenosine triphosphate (ATP) to move the ions to establish concentra-
tion gradients. If diffusion were the only force, then sodium gradually
Neurons Receive and Send Information 3
Table 1 Concentration of ions inside and outside animal cells.

ion intracellular concentration extracellular concentration
K+ 155 mM 4 mM
Na+ 12 mM 145 mM
Ca2+ 0.0001 mM 1.5 mM
Cl– 4 mM 120 mM
Source: Common knowledge. Additional negatively charged ions are also involved but
this is beyond the scope of this book.
phosphate group
2 potassium ions
cytoplasm
membrane
gamma beta
subunit subunit
A B extracellular
Figure 2 Primary and quaternary structure of a Na+/K+ pump. A,

Primary structure of one of three human Na+/K+ pumps encoded
by three genes. The protein contains about 1000 amino acids. B,
Tertiary structure of the same Na+/K+ pump in panel A, along with
two additional subunits, gamma and beta.
Source: Panel A is public domain. Panel B is public domain from PDB file 3B8E.
would diffuse into cells and potassium out of cells. The Na+/K+ pump
helps maintain the ion concentration gradients shown in Table 1. As with
many ion pumps, ATP is converted to adenosine diphosphate (ADP),
and the terminal phosphate is covalently added to the pump protein
on an aspartic acid, which is abbreviated D. The phosphate covalently
modulates the protein’s shape and thus changes its function. The discov-
ery of the Na+/K+ pump was rewarded with a Nobel Prize, but it took
many more years to discover how the pump moves charged particles in
opposite directions across plasma membranes. Physiologists in the 1960s
slowly uncovered how the pump functioned. First, they added each ion
to the pump in the presence of radioactive ATP to determine which ion
stimulates the pump’s phosphorylation. Only when sodium was added to
the cytoplasmic side of the pump did the pump bind to ATP and phos-
phorylate itself on the aspartic acid. Additional research over the next
20 years allowed physiologists and biochemists to completely diagram
how the Na+/K+ pump worked.
Neurons use electrical communication to move information down
their lengths as rapidly as possible. Chemical communication informs a
neuron what action it should take and what action it should pass on, such
as telling a muscle cell to contract. When neurons and muscles are resting,
they have thirty times more potassium in their cytoplasm than on the out-
side, and twelve times more sodium outside compared to inside. Na+/K+
pumps help maintain these ion gradients as a form of potential energy
that can be used later. For every ATP consumed, the Na+/K+ pump
moves three sodium ions out of the cell and two potassium ions into the
cell. This 3:2 ratio is a vital ion ratio because it contributes to the electrical
potential every animal cell on the planet needs to perform a wide range
of functions. By exporting one more Na+ than K+ it imports with each
Na+/K+ pump cycle, the cytoplasm gradually becomes more negative
compared to the extracellular world. One ion at a time, cells accumulate
an overall membrane potential, which is a separation of charged particles
in the form of Na+ and K+ ions. Animal cells have a resting membrane
potential in the range of −20 to −200 millivolts (mV), although the
precise number varies by cell type and species. The membrane potential
is also substantially maintained by a series of K+ ion “leak” channels not
discussed in this book.
Neurons that communicate to muscle cells at the neuromuscular junc-
tion have a resting membrane potential of approximately −70 mV, but
neurons are not “resting” to maintain these ion gradients. The membrane
potential is caused by a polarization of ions. All animal cells spend about
half of their energy maintaining ion gradients, so it may seem like an oxy-
moron to call these resting membrane potentials. When neurons are not
using electrical communication, they are described as resting, and the lack
of electrical activity is what is meant by “resting” membrane potential.
The Na+/K+ pump changes its shape in response to covalent modula-
tion when it is phosphorylated or dephosphorylated. Figure 3 illustrates
the steps. The pump (1) is allosterically modulated when it binds three so-
dium ions (2), which leads to ATP binding and phosphorylation (3). Once
Adenosine-PPP
1 P
ion pump
no ions 2 3
bound ion pump Adenosine-PP ion pump
3 Na+ 3 Na+ 3 Na+
(inside) bound bound
2 K+ (inside) 4
6 ion pump
ion pump 5 no ions
2 K+ bound bound
ion pump
2 K+ P 3 Na+
bound (outside)
P 2 K+ (outside)
Figure 3 Chemical activity of the Na+/K+ pump. Diagram of the

Na+/K+ pump cycle. Circles represent modulated states of the enzyme
and subsequent shape changes.
Source: Original art.
phosphorylated, the covalently modulated pump has a shape change in the

transmembrane domains and develops a low affinity for Na+. The pump
opens toward the extracellular world and lets go of the three sodium ions
toward the outside of the cell (4), which causes another shape change. Now
the pump has a high affinity for two potassium ions (5), which bind from
the extracellular environment to allosterically modulate the pump again.
Upon binding two potassium ions, the pump breaks its covalent bond to
the phosphate (6), which reverses the covalent modulation from step 3.
The transmembrane domains move again, close the opening on the extra-
cellular side, produce an opening on the cytoplasmic side, and the pump
develops a low affinity for K+. The pump releases the two K+ ions into the
cytoplasm, which allosterically modulates the pump again, and the cycle re-
peats (1). In completing the cycle, the Na+/K+ pump regains its high affin-
ity for sodium ions inside the cell, and the pump resumes its never-ending
cycle. The heart medication, digitalis, works by stalling a dose-dependent
subset of cardiac Na+/K+ pumps so that they cannot transport ions any
more. The net result is a reduction of membrane potential closer to −50 mV
with more sodium inside the cells than normal.
Neurons use the potential energy in the form of a membrane poten-
tial to produce an electrical current, which is the movement of charged
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particles. In Figure 1, the upper chemical communication box highlights

the area of neuron activation. A neurotransmitter ligand binds to its re-
ceptor on the neuron’s plasma membrane, which initiates a new form of
signal transduction (Figure 4). This neurotransmitter receptor is a ligand-
gated sodium channel. Ion channels bind to ligands and “gate” open
or closed because the structure of the ion channel functions as if it has a
door that can open or close. Once the ion channel gate is open, cells can
use the potential energy of ion gradients generated in part by the Na+/K+
pump. When the ligand binds, the ion channel allows only sodium ions
pore
beta delta
alpha subunit subunit
subunit
alpha alpha
beta subunit subunit
subunit
extracellular
gamma
subunit pore
membrane
delta cytoplasm
subunit
alpha gamma
subunit subunit
A top view B side view
open
extracellular closed extracellular ligand
cytoplasm cytoplasm
C D
Figure 4 Gated sodium ion channel structure and function. A, Channel

viewed from the extracellular side is composed of five subunits. B, Side
view of the same sodium channel but illustrated to show secondary
structures. Diagram of the gating mechanism that blocks (C) or
permits (D) Na+ to flow down its concentration gradient.
Source: Panels A and B are from PDB file 2bg9. Panels C and D are original art.
to flow down their chemical and electrical concentration gradients into

the cytoplasm. Ion channels are not as specific as enzymes, but they
are selective. Only ions of a particular charge and atomic radius can fit
through the pore of any given ion channel. Ion channels span the plasma
membrane, with ligand binding on one side and the transmembrane pore
within the phospholipid bilayer.
Once a Na+ ion channel opens, it allows positively charged Na+ ions
to move, producing an electrical current. When the polarization of ions
is reduced (extracellular Na+ ions enter the cell), then the membrane is at
least partially depolarized. Cellular current can be measured by placing
an electrode into a neuron and quantifying movement of ions across the
membrane (Figure 5). Rather than relying on a chemical signal to initi-
ate the current, investigators typically start their experiments by applying
electricity directly to the cell and then measuring ions rushing into the
neuron down the length of the axon. One benefit of using electricity to
stimulate neurons during experiments is that the level of input stimulus
input output
measure
neuron
A
applied
applied
current
current
+50 +50
potential (mV)
potential (mV)
membrane
membrane
time time
0 0
–50 –50
–70 –70
0 1 2 0 1 2
B time (ms) time (ms)
Figure 5 Stimulation and measurement of electrical current in

neuron. A, Stimulating electrode delivers known input current, and a
measuring electrode detects output current (membrane potential) at
its location along the axon. B, Two different stimulating inputs (10 or
20 mV) are applied to a neuron, and the resulting output membrane
potential is measured in the axon.
Source: Panel A is original art. Panel B is modified from Phillips et al., figure 17.2.
is easily controlled. Figure 5B shows the averaged results from repeated

experiments of applying each of two different levels of stimulating current
to neurons. When a cell was depolarized by only 10 mV (left side inset),
the measuring electrode (left side lower graph) detected exactly what was
applied to the cell, and the voltage decayed over time. However, when the
neuron was depolarized by 20 mV, the output current was much greater
than the input current, and the membrane potential increased by 120 mV
to a maximum of +50 mV. Through experiments similar to Figure 5,
physiologists had discovered that neurons require a threshold level of
stimulation before they will propagate their own electrical impulse
down their axons. When a neuron is stimulated at least as high as the
threshold, then the cell produces a complete wave of depolarization. In
further experiments, the physiologists found that no matter how much
above the threshold their input stimulation, the neuron always pro-
duced the same sized wave of depolarization in what has been called an
all-or-none response. Either the neuron is stimulated and it produces a
full depolarization (all), or threshold is not reached and the neuron fails
to produce its own depolarization wave (none).
Once biologists realized that neurons could be stimulated fully with
a threshold depolarization, they designed many more experiments to un-
derstand how cells propagate a wave of current (Figure 6). Investigators
stimulated a neuron once and simultaneously measured the membrane
potential at three locations along the axon. Electrodes further from the
activating electrode detected less depolarization. The investigators rede-
signed their experiment to measure membrane potential over a longer
time period (Figure 7). When they allowed enough time for the cell’s de-
polarization wave to travel down the axon, they detected the all-or-none
depolarization at every point down the length of the neuron. They called
this traveling wave of depolarization the action potential.
Ligand-gated ion channels densely populate a small portion of the
neuron’s plasma membrane where the chemical signal is first delivered.
Surrounding these ion channels and covering the vast majority of the
surface area on a neuron are a different type of gated ion channel called a
voltage-gated ion channel. As the name implies, voltage-gated ion chan-
nels open and close in response to depolarization of the membrane instead
of ligands binding receptors. At resting membrane potential, the sodium
applied
current
time
current generator
input
axon of neuron
measure
output
applied
applied
applied
current
current
current
time time time
Figure 6 Depolarization at one point in time. A neuron was

stimulated (top left) and the depolarization was measured (bottom
three probes) simultaneously at three distances from the site of
activation.
Source: Modified from Alberts et al., 1989, figure 19.12.
ions are more abundant outside a neuron, but once the membrane is lo-
cally depolarized to the threshold level or more, then the voltage-gated
sodium channels open. Like all proteins, these voltage-gated ion channels
do not know what is happening outside of their tiny local environment.
All they can sense is their structure as determined by the local charged
ions interacting with the side chains of their amino acids. Like ligand-
gated ion channels, voltage-gated ion channels behave like a drinking
fountain in that the fountain is always ready to let the water flow but the
fountain must be gated first. The voltage-gated ion channels are selective,
and the first wave of ion channels open to permit only Na+ ions to rush
into the neuron.
In Figure 5, threshold was approximately −50 mV, or a change of
+20 mV. At threshold depolarization, the voltage-gated sodium chan-
nels open, and they contribute further to the local depolarization until
the membrane potential is inverted to about +45 mV. Positive 45 mV
applied
current time
current generator
propogation
input
axon of neuron
measure #1 measure #2 measure #3

measure #1
measure #2
measure #3
0 1 2 3
time (milliseconds)
Figure 7 Depolarization over time. A neuron was stimulated (top

left) and the depolarization was measured over 3 milliseconds at three
distances (below neuron) from the site of activation.
Source: Modified from Alberts et al., 1989, figure 19.12.
represents the full depolarization for the cell in Figure 5. In Figure 7, the
depolarization wave moved down the length of the axon, and at each
position, the membrane potential reached +45 mV. The magnitude of
the action potential exceeded the initial stimulating voltage (+20 mV)
because once threshold was reached in a local area, all of the neighbor-
ing voltage-gated sodium channels opened and the membrane potential
was made less negative, causing more voltage-gated sodium channels to
open. As with any form of diffusion, intracellular sodium ions spread to

more voltage-gated sodium channels, and localized depolarization reaches
threshold again but in a new area. This process produces a full action
potential that will spread the entire length of the neuron. The duration of
a wave of depolarization is longer than the stimulating impulse because
many more ion channels open over time and allow more sodium ions to
diffuse to the next zone of voltage-gated sodium channels, which also
open in response to threshold depolarization.
To prevent an echo of the action potential from bouncing back to
the site of its origin, all voltage-gated sodium channels have a refractory
period of time when they cannot open even if the local threshold depo-
larization is exceeded (Figure 8). The area of depolarization has time to
repolarize (about −70 mV again) until the channels have “rested” long
enough to become responsive again to local depolarization. Neuronal ac-
tion potentials are one-way phenomena, and they do not move backward
to the area of the original stimulation.
Each ion channel permits about 1 million ions per second to move
from one side of the membrane to the other, which results in a rapid
rise in local ion concentration. Unlike ion channels, one Na+/K+ pump
completes its pumping cycle about 33 times per second, which results
in approximately 100 Na+ ions moved out every second. Sodium ions
rush into a neuron about 10,000 times faster than they can be removed
by pumps, yet a neuron can repolarize in milliseconds and not minutes.
cannot
open closed
extracellular Na+ channel extracellular K+ channel extracellular K+ channel
cytoplasm cytoplasm cytoplasm
A after depolarization B depolarized C shortly after depolarization
Figure 8 Neuron repolarization. A, Once closed, a voltage-gated

sodium channel cannot open again for a few milliseconds. B and C,
Voltage-gated potassium channels require threshold depolarization,
but their gating is time-delayed.
Source: Original Art.
Therefore, the neuron needs an equally fast mechanism to return the

membrane to the resting potential. It would be difficult to move Na+
ions back out quickly because the cell would be moving Na+ ions into a
Na+-rich area. Na+ ions would not rush back out via passive diffusion as
fast as they rushed in. Scattered among the voltage-gated sodium chan-
nels are counteracting voltage-gated potassium channels. With the cyto-
plasm now positively charged, compared to the outside, and the chemical
gradient of K+ ions shown in Table 1, K+ ions experience electrical and
chemical gradients to leave the cell (Figures 8B and 8C). Voltage-gated
sodium channels opened immediately upon threshold depolarization,
but voltage-gated potassium channels opened a few milliseconds after the
threshold depolarization has been reached. Because K+ ions pass through
their voltage-gated K+ channels at about 1 million ions per second, the
membrane repolarizes by the exodus of K+ ions as quickly as it depolar-
ized but with a slight time delay due to the time difference of opening for
Na+ and K+ ion channels.
Depolarization and repolarization occur within milliseconds of each
other, but this presents a new problem. Before a neuron can generate a
new action potential, it must reestablish the ion gradients in Table 1.
Neurons are ready to fire again in less than a second. The rate of blink-
ing is controlled by the rate of action potentials moving through neurons
and communicating to muscles. The only protein available to pump K+
ions back into the nerve cell and Na+ ions out again is the same Na+/K+
pump that contributed to the resting membrane potential in the first
place. Millions of ions have to be pumped at the expense of ATP which
helps explain why nearly half of a cells’ energy is spent maintaining the
ion gradients in Table 1.
Neurons need hundreds of more Na+/K+ pumps than voltage-gated
sodium channels to match ion transport rates. Different membrane pro-
teins must be produced in different amounts, and their densities in the
plasma membrane can vary over several orders of magnitude. Action
potentials do not echo backward because the Na+ ion channels have
a refractory period, so they cannot reopen immediately toward the ac-
tion potential’s origin. Furthermore, mixed among the voltage-gated
Na+ channels are voltage-gated K+ channels which quickly regenerate a
net negative charge in the cytoplasm. The density of voltage-gated Na+
electrode
measures
current
electrode “clamp”
membrane patch
axon plasma membrane
Figure 9 Patch clamp method measures single channel activity. Pipet

removes a patch of membrane containing one ion channel.
channels and voltage-gated K+ channels are approximately equal. They

both facilitate ion movement at about the same rate. The much more
abundant but slower Na+/K+ pumps help reset a neuron before it can be
activated again by a new ligand binding to the ligand-gated ion channels
that can initiate a new action potential. These four types of proteins (a
ligand-gated ion channel, two voltage-gated channels, and an ion pump)
play important roles in the electrical communication in neurons.
A neuron’s function is the cumulative response of hundreds of thou-
sands of individual proteins working independently. Physiologists discov-
ered that a very small pipet tip placed onto the plasma membrane of
a neuron can pull off a patch of membrane and hold it in the narrow
opening (Figure 9). The patch clamp method allows scientists to watch
the activity of one or a few ion channels at a time instead of the averaged
response of an entire cell. By isolating only one channel in a patch of
membrane, they could watch the current fluctuate as the lone gate opens
and closes. When one ion channel opens, the current goes from zero to
2 picoamps (pA). If a second channel were present, the current could rise
to 4 pA. An ion channel does not stay open for a constant amount of
time. The duration of an open channel ranges from about 1 millisecond
to over 10 milliseconds. This variability of open times indicates that ion
channels are inherently noisy and that random movements of amino acid
side chains play a role in the channel’s behavior.
If three ion channels were independently stimulated by a defined elec-

trical input, they would not open and close synchronously. One channel
might close very quickly, another might partially closed three times, and
the third one might opened once but stayed open consistently. An ac-
tion potential is the summation of many individual ion channels from
a population of voltage-gated sodium channels. Eventually, all of the
channels will close and enter their obligatory refractory period before the
stimulating input has ended. Action potentials in neurons result from
many voltage-gated sodium channels followed by many voltage-gated po-
tassium channels and many more Na+/K+ pumps to help the ions return
to the gradients in Table 1.
A neuron conducts electricity down its length as a consequence of
thousands of ion channels and pumps. Neurons communicate electrical
information like a copper wire carries information in the form of electri-
cal current. However, vertebrates and some other species have evolved
a cellular insulation that enhances the rate of electrical communication
down axons (Figure 10). Nerve cells that appear white in animals are
covered by insulating cells, called Schwann cells, that form a lipid-rich
myelin sheath surrounding the axons. The myelin sheath is more than
just insulation, because myelinated axons conduct electricity faster than
non-myelinated axons of the same diameter.
Electron micrographs reveal that myelin is composed of a Schwann
cells’ extended membrane wrapping around the axon 20 to 30 times to
produce a hydrophobic, fatty insulation. The Schwann cell’s multi-layered
axon of nerve cell
myelin from Schwann cell
Figure 10 Myelinated axons conduct electricity faster than non-

myelinated axons. Diagram of two axons and how myelin accelerates
the conductance of electricity in myelinated nerves.
plasma membrane wrapping produces an insulator of sufficient thickness

to ensure that the ions do not leak from the axon but not so thick as to
waste cellular resources. Myelin insulation is not continuous for the entire
length of the axon. There are gaps between adjacent Schwann cells called
nodes of Ranvier, named for the man who discovered them in 1867.
Holes in the insulation are not harmful to its function. Instead, neurons
use a saltatory movement of ions across the plasma membrane to propa-
gate the action potential. Without extracellular Na+ ions near sodium
channels, a neuron could not use electricity to communicate down its
axon. The nodes of Ranvier allow neurons to transmit their electrical cur-
rent faster skipping every other step when racing up stairs. Slower, non-
myelinated neurons conduct electricity by small steps of Na+ and K+ ion
flow. Myelinated axons can skip the intermediate steps and jump faster
from one node of Ranvier to the next. The optimal distance between
nodes is determined by the rate of Na+ ion diffusion in the cytoplasm
of axons, and the threshold of voltage-gated ion channels clustered at the
nodes and absent from areas covered by Schwann cells.
Ion channels flick open and closed with random timing making it im-
possible to predict when a particular channel will open next or how long
it will stay open. However, while the channel is open, the current always
reaches the same magnitude because ions are rushing through the channel
at maximum velocity and cannot go any faster. The summation membrane
protential response of an action potential will terminate even if stimulus
persisted. The reason the current ends is that gradually, the collection of ion
channels enter their refractory period and cannot open again until later. By
the time the refractory period is over, the original stimulus has been termi-
nated and only a single action potential will travel the length of the neuron.
The benefit of myelin is only realized if nodes of Ranvier are appropri-
ately spaced. The spacing of the nodes allows waves of sodium to flood the
axon cytoplasm and spread to the next node where more voltage-gated
sodium channels are available to open. The myelin covers most of the
membrane, so ions cannot enter the cytoplasm except at the nodes. In
axons of the same diameter but without myelin, all of the ion channels
can open, and it takes longer for the action potential to gradually move
down the axon because incremental movement would be much shorter
than the bigger steps between Nodes.
The nerve impulse began with a chemical signal that activated

ligand-gated sodium channels to initiate the electrical communication.
Voltage-gated sodium channels propagate the signal down the axon,
while voltage-gated potassium channels reverse the depolarization.
With the benefit of myelin, axons send the action potential faster to
their terminal ends where the cells produce a new chemical signal to
communicate with the muscle cell. At the end of the action potential,
depolarization reaches the terminal plasma membrane. Located at the
terminal ends of axons are yet another type of ion channel—voltage-
gated calcium channels. These calcium channels are required to con-
vert the electrical signal back into a chemical signal that will reach the
neighboring cell.
The movement of Ca2+ ions through calcium channels at the nerve
terminus can be measured in a way that does not disturb the cell, unlike
the patch clamp method that kills the cell from which the patch was
taken. It is possible to load the cytoplasm of live cells with a fluorescent
dye that changes color depending on the concentration of Ca2+ ions.
Computers can covert the Ca2+ ion concentration to a rainbow color
scale from dark blue, which represents no detectable Ca2+, all the way
to red, which represents the highest levels of Ca2+ ions. While watch-
ing these neurons in real time through a microscope, investigators can
stimulate a neuron on one end and view the opposite end to see what
happens when the action potential arrives at the terminus. The nerve ter-
minus at the neuromuscular junction is flooded by calcium ions (turn-
ing the microscopic image red), because voltage-gated calcium channels
in the plasma membrane opened in response to the action potential and
the Ca2+ ions rushed down their electrical and chemical concentration
gradients (Table 1).
The action potential has been converted from a wave of sodium ions
to a terminal wave of Ca2+ ions. Both ion waves represent electrical cur-
rent rather than a chemical message that can be passed to the next cell.
To secrete its neurotransmitter neurons must perform a process called
exocytosis. Exocytosis causes cells to secrete molecules to the extracellular
environment because the membranes that form vesicles which contain
neurotransmitters fuse with the plasma membrane. During exocytosis,
the secretory vesicles release their contents to the outside the cell. At
the termini of axons, neurons accumulate secretory vesicles that contain

neurotransmitters similar to the chemical messengers that started their
own electrical signal. Exocytosis must be a tightly regulated process or
neurons would tell muscles to contract at times other than when they
were supposed to contract. Regulated exocytosis is initiated by a rise
in cytoplasmic Ca2+ ions, which is produced in response to the action
potential. The trigger for regulated exocytosis is a Ca2+-binding protein
located in the membranes of secretory vesicles. To determine the loca-
tion of the Ca2+-binding protein, investigators performed an experiment
where they applied antibodies tagged with tiny gold beads to thin slices of
the termini of neurons and then visualized the experimental results with
an electron microscope. The Ca2+-binding protein is located wherever
they saw multiple black dots—on the outside of the secretory vesicles.
Once this protein binds Ca2+, it changes its shape through allosteric
modulation. The new protein shape allows it to interact with comple-
mentary proteins on the plasma membrane, so they adhere to each other.
As long as the nerve terminus has elevated Ca2+ ions, it will continue to
secrete neurotransmitter to the neighboring cell. Once the action poten-
tial stops, calcium is pumped out of the cytoplasm, exocytosis stops, and
the adjacent cell is no longer bombarded with neurotransmitters.
Voltage-gated Ca2+ channels fill the small volume of neuron’s termi-
nus with enough Ca2+ to initiate regulated exocytosis. In order to stop
secreting neurotransmitter, the neuron must be able to rapidly reduce the
concentration of Ca2+ ions. The Ca2+ ion gradient in Table 1 had been
established by Ca2+ pumps located in the plasma membrane. Therefore,
all of the Ca2+ that flooded the cytoplasm from outside the cell must be
returned rapidly back to the extracellular environment in order stop exo-
cytosis. Because pumps move ions more slowly than channels, there must
be many pumps for every one voltage-gated Ca2+ channel.
Embedded in the membrane of a neuron’s secretory vesicles are pro-
teins that can bind Ca2+. Their Ca2+ binding sites are located in the cyto-
plasm and not inside the lumen of the vesicles because the increased Ca2+
ions are located in the cytoplasm. A rise in Ca2+ leads to a new protein
shape and the fusion of secretory vesicles to the plasma membrane. Upon
fusion, a tunnel or opening forms between the membrane of the vesicle
and the plasma membrane of the cell, and the opening grows in size until
the vesicle becomes part of the plasma membrane and its contents are
completely outside the cell.
Every activated neuron goes through the same three steps: 1) receive
a chemical message; 2) produce an electrical current that causes an action
potential to move down the axon; and 3) produce a new chemical mes-
sage to secrete via exocytosis. Action potentials are waves of Na+ ions that
jump from one node of Ranvier to the next in myelinated neurons. At
the end of the axon, calcium floods the cytoplasm, which triggers regu-
lated exocytosis of the neurotransmitter chemical messenger. Nerve to
muscle communication is very complex, but every animal performs the
same process for every movement. The next chapter describes how similar
neurons and muscles are with regard to their shared use of action poten-
tials and ion concentration gradients.
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synaptotagmin and synaptophysin are sorted to separate cellular com-
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Glynn IM. Annual review prize lecture: all hands to the sodium pump. J
Physiol 462:1–30, 1993.
Horn R, Patlak J. Single channel currents from excised patches of muscle
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Jiang Y, Lee A, Chen J, et al. X-ray structure of a voltage-dependent K+
channel. Nature 423(6935):33–41, 2003.
Lemas MV, Hamrick M, Takeyasu K, et al. 26 amino acids of an extracel-
lular domain of the Na,K-ATPase a-subunit are sufficient for assembly
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1994.
Long SB, Campbell EB, MacKinnon R. Crystal structure of a mamma-

lian voltage-dependent shaker family K+ channel. Science 309(5736):
897–903, 2005.
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the sodium-potassium pump. Nature 450(7172):1043–1050, 2007.
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enosine triphosphate-dependent sodium and potassium transport
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www.Ebook777.com
CHAPTER 2
Muscles Contract and

Grow Bigger
Vertebrates have three types of muscle cells: smooth, cardiac, and

skeletal (Figure 11). Cardiac muscle is found in the heart. Smooth
muscle is found in the walls of many organs—where it regulates blood
flow, moves food through a person’s digestive tract, and helps with other
essential functions. Skeletal muscle makes up the bulk of a person’s
muscles and is attached to the skeleton. Neurons can tell muscles when
to contract. In healthy animals, skeletal muscles get bigger when the are
cardiac muscle cells
skeletal muscle cells
smooth muscle cells
Figure 11 Muscle anatomy and structure in three types of vertebrate

muscle cells: a cardiac muscle cell (top), a skeletal muscle cell
(middle), and a smooth muscle cell (bottom). Note that the skeletal
muscle cell has multiple nuclei, whereas the other types have only one
nucleus per cell.
contracted repeatedly over many days. This Chapter will focus on how
muscles contract and whether they grow in size by adding more protein
or by increasing the number of cells.
Neurons that communicate directly with skeletal muscle cells are
called motor neurons. Skeletal muscle contraction is under voluntary
nervous system control such that muscles contract when neurons secrete
the neurotransmitter acetylcholine onto the muscles. Muscles are mul-
tiple bundles of muscle cells held together by connective tissue. Skeletal
muscle is composed of long cylindrical cells composed of a repeating unit
called a sarcomere. Each sarcomere begins and ends with the thin black
stripe in the middle of a light region. The repeating pattern of sarcomeres
is what causes the striated (striped) pattern of skeletal and cardiac muscle
cells in Figure 11.
Skeletal muscle cells are very unusual because of their gigantic size
and their extensive production of proteins used to contract muscles.
Skeletal muscles are also unusual because they are multinucleated, mean-
ing each cell can contain hundreds of nuclei. Muscle cells are the product
of many smaller precursor cells fusing together. The number of nuclei
in a muscle cells indicates how many precursor cells fused to form the
much bigger muscle cells. The number of nuclei varies depending on
how big the muscle cells are. Longer muscles will contain longer cells and
therefore more nuclei. A muscle is the summation of many long, skinny
muscle cells bundled together to function as a cohesive tissue. Within
each cell are the repeating sarcomere units. Each multinucleated muscle
cells contains hundreds to millions of sarcomeres, depending on the size
of the muscle cell.
Sarcomeres are the smallest functional unit of the muscle. When a
muscle contracts, each sarcomere gets shorter and pulls the neighboring
sarcomeres closer together. With all the sarcomeres working together, the
entire muscle cell shortens. When all of the cells shorten at the same time,
the overall muscle contracts. If all of the muscles cells are instructed to
contract by a coordinated effort from many neurons, a person can execute
complex body movements.
Scientists who discovered how muscles function had to analyze mi-
croscopic images that reveal what happens inside a muscle cell once its
plasma membrane is depolarized. The cut three-dimensional muscle cells
Muscles Contract and Grow Bigger 23
longitudinal section 3D perspective cross sections
Figure 12 Visualizing 3D objects when cut at different angles. A

doughnut is on top and a hand is below. Longitudinal sections (left
column) are easier to visualize than cross sections. Arrows in the
center column show where the cross sections were made (right
column).
from different angles (Figure 12). Longitudinal sections are easily iden-
tified, whereas cross sections are more cryptic. Only by studying many
different cross sections could the scientists assemble a mental picture of
the original 3D object.
Skeletal muscle cells in Figure 11 have multiple nuclei and the sarco-
mere repeats, or striations. The longitudinal view of muscle cells reveals
light and dark stripes within one sarcomere. A sarcomere cut in cross
section and viewed with an electron microscope would reveal individual
proteins that form the stripes within the dark and light bands of the sar-
comere. In a cross section, the proteins look like the ends of two sizes of
pencils bundled together. Using hundreds of photomicrographs, biolo-
gists pieced together the molecular components of muscle contraction.
Sarcomeres are composed of two major protein types, dark and light
rods. The thicker dark rods form the central dark band of the sarcomere,
whereas the lighter protein rods form the two light bands on either side
of the dark band in the middle. The positioning of the dark and light
protein rods in the cross section is not random. The thicker protein rods
one sacromere
myosin polymer filaments
anchored ends free ends of

of actin filaments actin filaments
Figure 13 Actin and myosin interactions provide contractile function.

A sarcomere is the length of a contractile unit that spans from one
actin anchor to the next.
are distributed in hexagonal patterns with one dark rod in the middle.
Furthermore, six lighter protein rods surround each darker protein rod to
produce a maximally packed interleafing of two proteins that are essential
to muscle contraction. By analyzing thousands of electron microscope im-
ages of sarcomeres, biologists have assembled an accurate model of the two
rod proteins—lighter actin and darker myosin (Figure 13). The molecular
cause of the light and dark bands as well as the area where actin and myo-
sin overlap is revealed in the areas of one or both of the rod-like proteins.
Actin polymers twist around a central axis analogous to the helix of
DNA. Actin polymers spiral and present a series of slightly flattened faces
around the outer surface of the polymer. The dark protein rod of myosin
is also a polymer, but it is harder to discern the monomer units. The com-
posite myosin rod has a series of lobes distributed all around the cylindri-
cal rod. Each dark myosin rod is composed of many monomers shaped
like a long-stemmed cloverleaf with only two lobes. The lobes on myosin
can reach across the space separating actin and myosin and attach to the
flat spots on actin polymers. When a muscle contracts, the light band of
actin gets smaller while the dark band of myosin stays the same size. The
overall size of the sarcomere is reduced because the dark vertical lines
anchoring the actin polymers are drawn toward the center of the myosin
rods.
Myosin consumes ATP to harvest the energy from the covalent
bond holding on to the third phosphate. Myosin is a molecular motor
that binds to actin and pulls the actin. Myosin reaches out and pulls
the actin polymers toward the center of each sarcomere. All of the sar-
comeres are attached to each other, so they all squeeze together and the
muscle cells contract. Consuming ATP’s energy, and producing ADP
plus the terminal inorganic phosphate (Pi), powers myosin’s pulling.
Each round of myosin binding, pulling, and releasing actin is one con-
traction cycle that consumes one ATP. When ATP binds to myosin,
the myosin molecule releases its grip on actin. Shortly after binding
to myosin, ATP is cleaved into ADP and Pi, which causes the myosin
to “reload” its spring-like lever and bind to actin again. Once myosin
binds, it releases Pi, which initiates the spring-like action of myosin to
pull the actin. Finally, ADP is released, creating a fresh site for ATP
to bind and release myosin from actin. The myosin cycle is rapid with
about six ATPs consumed by a single myosin molecule every second.
Take the number of myosin monomers on a single myosin polymer and
multiply that by the number of myosin polymer rods in a single muscle,
it is easy to see why muscles require so much energy and produce so
much heat when exercised.
In cross section, myosin rod polymers are surrounded by actin on six
sides, which ensures that myosin lobes will always have an actin bind-
ing site nearby. Each myosin polymer extends myosin arms in multiple
directions so that each myosin can reach one of the six actin polymers
surround it. Similarly, the spiral nature of the actin polymer ensures that
a myosin binding site will be facing in six directions and thus facilitate
myosin binding from all six sides.
Muscle contraction occurs when millions of sarcomeres contract. As
myosin pulls on actin, the two light bands of actin are drawn toward
the central dark band of myosin. The light bands on both sides disap-
pear because actin polymer rods are sliding between the myosin polymer
rods, which do not move. The myosin rods do not move because there
are equal numbers of myosin molecules on both ends pulling in opposite
directions. The thinner, rope-like actin polymer rods are pulled by myosin
toward the center of the sarcomere from either side.
Muscles contract constantly as long as ATP is available in muscle cells,
which is most of the time. Muscle relaxation is regulated by two addi-
tional proteins that are physically associated with actin rods—troponin
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actin troponin tropomyosin
10 nm
Figure 14 Troponin and tropomyosin regulate muscle contraction.

Actin rods are covered by long tropomyosin fibers and regularly
spaced troponin molecules. Troponin binds calcium, which causes
tropomyosin to stop blocking the myosin binding sites on actin.
Source: Original Art from common knowledge.
and tropomyosin (Figure 14). Tropomyosin binds to actin and blocks

the myosin binding sites. Troponin binds to tropomyosin and has a very
high affinity for calcium. When a muscle cell is stimulated to contract,
its plasma membrane is depolarized (by a neurotransmitter), which opens
calcium channels to flood the muscle cytoplasm with calcium ions (Ca2+).
Troponin binds to calcium and changes its shape which causes tropomyo-
sin to move away from the myosin binding sites on actin. Calcium bind-
ing to troponin when muscles are flooded with Ca2+ determines when
muscles can contraction.
Skeletal muscle contraction is initiated when neurons release the
neurotransmitter acetylcholine onto muscle cells. A muscle cell’s plasma
membrane contain acetylcholine receptors (ligand-gated sodium chan-
nels) that initiate action potentials on muscle cells. Muscle cells also pos-
sess unusual extensions of their plasma membranes, called T-tubules,
to direct the action potential throughout the thick muscle cytoplasm
(Figure 15).
The transverse tubules (T-tubules for short) extend into the cytoplasm
much like sewer pipes run under roads and sidewalks. The T-tubules are
pressed closely against the sarcoplasmic reticulum (SR; as in sarcomeres)
which is a modified endoplasmic reticulum in muscles cells. The SR is a
vast storage organelle for Ca2+, which releases its Ca2+ when stimulated
by an action potential from the adjacent plasma membrane T-tubule.
When the stimulating action potential leaves, the SR retrieves the cal-
cium with the help of a calcium pump similar to the sodium/potassium
openings of T-tubules
plasma
membrane
sarcoplasmic
reticulum
actin &
myosin
T-tubule
Figure 15 Membrane network surrounding sarcomeres. Diagram

of part of one muscle cell showing how the plasma membrane
makes tunnels (T-tubules) through the cytoplasm. T-tubules abut
an organelle called the sarcoplasmic reticulum (SR) which stores
calcium away from the cytoplasm.
pump in the plasma membrane of neurons and muscle cells. Action po-
tentials on a muscle cell’s plasma membrane causes contraction because of
calcium’s effect on troponin. When stimulated to contract, a muscle cell’s
cytoplasm is flooded with Ca2+ from the SR, and Ca2+ binds to troponin.
Troponin is allosterically modulated by Ca2+ to change its shape, which
causes tropomyosin to move off the myosin binding sites on actin, allow-
ing muscles to contract.
If muscle cells possessed normal plasma membranes without
T-tubules, the action potential could only reach SR membranes on
the surface of the muscle cells, and the Ca2+ ions would slowly dif-
fuse through the muscle, leading to a slow and uncoordinated muscle
contraction. By winding throughout the cytoplasm, T-tubules ensure
the depolarization message reaches the entire cell with the speed of an
action potential. Relaxation is permitted by the return of Ca2+ to the
SR, troponin reverting back to its previous shape, and tropomyosin
covering the actin binding sites.
Muscles physically grow in response to frequent use. There are two
types of growth possible, hypertrophy or hyperplasia. Hyperplasia is
what happens in cancer-cell proliferation. Skeletal muscle cells are un-
usual in that they are the consequence of many, many cells fusing together.
That’s why skeletal muscles have so many nuclei in a shared cytoplasm.

Skeletal muscles do not go through mitosis and cytokinesis the way most
cells do. Hyperplasia in skeletal muscles happens when new cells fuse to
make new muscle cells or increase the size of existing muscle cells. The
cells that fuse to muscles are produced by nearby stem cells that are not
depleted.
Scientists performed experiments to understand how muscles get
bigger using rats as their study organism. They caused one muscle (plan-
taris) to grow rapidly by removing another muscle (b) from the hind
legs of young male rats. The gastrocnemius is the large calf muscle, and
the plantaris is much smaller located closer to the knee joint, under-
neath the larger gastrocnemius. These two muscles perform very similar
movements, so removal of larger muscle caused the smaller muscle to
grow in size similar to changes that happen when any muscle is exercised
repeatedly.
The scientists removed the gastrocnemius muscle from the left legs of
twenty rats. The right legs were operated on in a sham procedure where
the surgeons did everything the same except they did not remove the
gastrocnemius. The investigators sacrificed rats 5, 30, or 60 days after
surgery and removed their plantaris muscles from both legs to dry and
weigh them (Figure 16). The physiologists also quantified the amount of
DNA in the muscles.
It is important to note that the rats were young, so plantaris mus-
cles on both legs grew larger during the course of the experiment. The
plantaris muscles on the left side were heavier than same muscles from
the sham-operated right side. The total muscle mass from left plantaris
muscle appears to be significantly larger than the control muscle after
60 days. The mass of the plantaris muscle DNA also increased, but the
DNA mass is about 0.001 that of the total dry mass. Most of the mass
is protein and the most abundant proteins in muscles are actin and
myosin. The increase in actin and myosin indicates the muscles grew
mostly by hypertrophy. Muscle cells do not divide like most cells so the
increased DNA indicates new cells fused with the existing muscle cells,
which is a skeletal muscle’s form of hyperplasia. The muscles increased
their size with more protein (hypertrophy) and DNA (hyperplasia)
simultaneously.
plantaris dry mass (mg ± 1 stdev)

1000 = left leg
= right leg
800
600
400
200
800
plantaris DNA (µg ± 1 stdev)
600
400
200
0
5 30 60
days after surgery
Figure 16 Effect of removal of the left gastrocnemius muscle on the

left plantaris muscle in 20 rats. Right leg was the control side. (top)
Plantaris dry mass +/− SD. (bottom) Total muscle DNA +/− SD.
Source: From Hubbard et al., 1975, Table 1.
Ethical, Legal, and Social Implications: Use of

Performance Enhancing Drugs
Recent scandals of professional athletes taking performance-enhancing
drugs (PEDs) have brought to light the issues involved in PEDs, many
of which have not been tested adequately for safety or efficacy. The use of
PEDs is not limited to sports. Students and professionals frequently use
chemicals to gain an advantage in their performance and productivity.
A variety of chemicals taken by athletes can lead to muscle growth and
increase endurance, strength, or power. Testosterone is a normal human
growth hormone produced by men and women. Because testosterone is

a male sex hormone, males typically produce more of it and tend to ex-
hibit increased muscle mass more readily than women. Bolstering natural
testosterone levels with injections can increase muscle mass in male and
female athletes. The use of testosterone is banned in many sports, and its
use is illegal in some countries.
Steroid injections can produce undesirable side effects, such as behavioral
changes as well as heart attacks and liver cancer. In the course of training and
playing, top athletes routinely push themselves to the brink of injury and
thus may accept additional risks to improve their performance. These athletes
are willing to accept the additional risks of PED side-effects and argue that
they have the right to determine how much risk is appropriate for them. In
a truly free society, individuals are free to make choices that others consider
to be poor decisions. Does personal freedom justify the use of potentially
dangerous drugs? Many athletes who might not otherwise take PEDs do so
because they know that other athletes are. To compete successfully, they feel
compelled to take PEDs. Should children be allowed to use PEDs if they
want to? If so, at what age? Who should decide, the child or the parents?
In the 1960s, the International Olympic Committee (IOC) estab-
lished rules to prevent use of PEDs to protect the health of athletes and
ensure fairness for all athletes. Olympic athletes must submit urine for
testing of banned substances. Sometimes, even gold medal winners are
forced to return their medals when they are caught cheating. Opponents
of PEDs want more athletes to be tested for these drugs with harsher
penalties for detection. The anti-PED movement wants improved drug
education programs providing information and skills to athletes to allow
them to make responsible and healthy decisions. Proponents of PEDs
argue that a lot of money is wasted on testing programs that are futile.
Each year, athletes find new ways to avoid detection, such as using some-
one else’s urine. Furthermore, new drugs are being developed that are
undetectable, but no one knows if the drugs are harmful or not.
Because PEDs are used furtively, their use is unregulated and uncon-
trolled, and PEDs are often being used by athletes that do not fully under-
stand how they work. In the absence of understanding, many people use
a “more is better” approach to PEDs. Legalization would permit uniform
education for athletes and regulation of which PEDs can be used and how
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much. A better use of testing program money might be to develop safer PEDs
that could be sanctioned by sports authorities. If PEDs were allowed within a
particular sport, universal access would level the playing field. Ironically, the
stated reason for taking PEDs in the first place is to gain an advantage, and
this would no longer be true if every athlete had equal access to the PED.
Sanctioned PEDs would satisfy the IOC’s equality principle, but not every
athlete would have equal access to the drug due to costs, availability, or health
concerns. Furthermore, because steroids regulate gene activity, it is not clear
that it would ever be safe to inject steroids above normal levels.
For many purists, PEDs violate the spirit of athletics, fail to recognize
the natural talents of athletes, and lead to a pharmaceutical arms race by
the athletes. If the authorities who make the rules consider the use of
PEDs to be cheating, then athletes using PEDs are successful without
putting in the hard work. Rules can change, but under today’s rules, using
PEDs to gain an advantage is cheating.
Rules banning PEDs are in place for the safety of athletes, even in
more dangerous sports where injuries occur with higher frequency. Some
people see athletes as role models, and role models that cheat are effec-
tively endorsing cheating. Although society bans PEDs from sports, drug
use in other areas is condoned. Alcohol, tobacco, caffeine, and cocaine
are tolerated to different degrees by different segments of society. Health
concerns seem to fade away with prescription drugs for energetic children
or PEDs by students cramming for finals. Should the same health and
fairness standards to drug use outside of athletics?
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Annu Rev Cell Biol 3:379–421, 1987.
CHAPTER 3
Memories Require New

Proteins in Neurons
Learning and memory are two of the great wonders of biology. Put a
bunch of neurons together, allow them to communicate, and learning
and memory arise, but how? Ancient philosophers and modern biologists
tried to determine how memories are formed. Eric Kandel from Colum-
bia University in New York City wanted to understand memory forma-
tion in part because of a vivid, traumatic memory that remains with him
from his childhood. Kandel was born in Vienna Austria in 1929 and fled
with his family in late 1930s after the Nazis took control of the city. The
violence he and other Jews observed was etched into his memory. In his
Nobel Prize biography, he says these intense memories encouraged him to
study psychiatry in medical school, but he became attracted to the biol-
ogy of the mind. Rather than practice medicine, Kandel became a bench
scientist to learn how memories are formed.
Kandel took care when choosing his model system for memory and
chose a very simple animal—the sea slug of the genus Aplysia. Kandel
studied how the sea slug learned to protect itself from harm. Aplysia lives
underwater and breaths through gills. Just as fish gills are covered to pro-
tect them, Aplysia has a fleshy envelop called a mantle that surrounds and
protects the gill from physical harm. The slug brings in water over its gill
and pumps out the water through a siphon, which protrudes beyond the
mantle. When Kandel touched the siphon with a pointed object, Aplysia
withdrew its siphon and its gill to protect them from harm. If Kandel
touched the siphon shortly after applying a mild electrical shock to the
tail, the animal retracted the siphon and gill to a greater extent. Follow-
ing this shock/touch training, when Kandel lightly touched the siphon in
the absence of a shock, the animal responded as if it has been shocked. In
other words, the sea slug learned to associate the shock with the touch.
The memory of the electrical shock lasted about 1 hour and then faded,
which is an example of short-term memory. However, if the animal was
trained with one shock a day for 4 days, Aplysia retained the memory of
being shocked for several days. Animals increased the duration of gill
and siphon withdrawal following four trainings sessions a day, and the
memory persisted even longer. Memory that persists longer than just a
few hours is considered long-term memory.
When Kandel began working with Aplysia, biologists had already
established that neurons were responsible for learning and memory.
Furthermore, physiologists documented that sensory neurons bring in-
formation into the animal, whereas motor neurons send signals that cause
muscles to contract. Kandel was able to find the sensory neurons that
transmitted information from the siphon as well as the motor neurons
that cause the gill to retract. Kandel numbered all the neurons in a clus-
ter located within the body of Aplysia; those on the left side started with
the letter L. With stimulating and measuring circuitry in a single pipet,
Kandel could stimulate any neuron individually and measure the action
potential of the same neuron or a different neuron using an second elec-
trode. Kandel also measured the contraction of the muscle connected to
the gill using a second instrument.
The purpose of the electrical shocks to the tail was not to cause mus-
cles attached to the gill and siphon to contract. The shock provided a
noxious stimulus that the slug could learn to associate with touching of
its siphon. The investigators could have pinched the animal’s tail, but
electrical shocks were easier to reproduce and deliver. Once the animal
was trained, no electrical shock was used to measure learning. The gill
was retracted further and for a longer time with more training because
the animal retained the memory that associated an unpleasant sensation
with the gentle touch to its siphon. Learning does not require electrical
shocks; any noxious stimulus could have been used. Electrical shocks were
convenient and permitted careful regulation over their intensity so that
the animal would not be hurt.
The investigators stimulated neuron L7 about 20 times in rapid suc-
cession and measured the gill’s retraction in response. Kandel and his
collaborators stimulated the sensory neuron LE and then measured the
Memories Require New Proteins in Neurons 35
action potential in motor neuron L7 communicating with the gill muscle

in response to the information passed from LE to L7. Finally, the investi-
gators stimulated LE many times, and measured the response in L7 and
the retraction of the gill in response to muscle activation by L7.
There are two ways skeletal muscles can be prompted to contract.
The conscious way is for the brain to initiate a signal to move a particular
muscle. Conscious contraction differs from reflexive muscle movement
which bypasses the brain completely as when tapping the tendon below
the knee and causing the leg to jump. In Aplysia, gill retraction is a reflex
executed by 24 sensory neurons collecting information from the siphon
and six motor neurons telling the gill muscle to contract. Reflexive behav-
ior is not learned, it is hardwired into the animal. But training the gill to
retract more forcefully and stay retracted longer after shocking the tail is
a learned behavior.
The major players in the learned behavior of gill retraction are a small
group of neurons that use the neurotransmitter serotonin to communi-
cate directly with the sensory neurons (Figure 17). Learning is possible
because the serotonin neuron from the tail alters the sensory neuron that
is part of a simple linear reflex neuronal circuit between siphon and gill.
This chapter focuses on the simple learning circuit of gill retraction, but
there are additional neurons not shown that provide subtlety to memory
formation. Serotonin is produced by invertebrates and vertebrates, as
well as by fungi and plants. Calling serotonin a neurotransmitter is cor-
rect, but it also functions as a signaling molecule in organisms that don’t
have neurons.
From the standpoint of understanding memory formation and learn-
ing, humans use the same molecules that Aplysia uses. The serotonin neu-
ron communicates with the sensory neuron that tells the gill muscles to
retract. The key element of learning is that the same light touch to the
gill that used to produce a mild retraction now produces a much stronger
retraction. The sensory neuron’s output has been altered because of its
interaction with the serotonin neuron. The altered output of the sensory
neuron is evidence of a memory in Aplysia.
Memory comes in two forms—short term and long term. Short-term
memory is the consequence of minimal stimulatory input, whereas long-
term memory is the consequence of repeated input. Short-term memory
www.Ebook777.com
siphon
tail
serotonin SN
MN
gill
Figure 17 Neural circuit connecting tail shocks to learned behavior of

gill and siphon retraction. The first neuron secretes neurotransmitter
serotonin to communicate with sensory (SN) that communicates with
the motor (MN). The gill retracts when SN detects that the siphon
has been touched.
Source: Modified from Kandel, 2001, his figure 2C.
only lasts for minutes to a few hours, whereas long-term memory lasts
from days to years. Short-term memory does not require any new pro-
tein production but long-term memory does. These distinctions between
short- and long-term memory were key insights that opened the way
for Kandel and his collaborators to understand how neurons produce
memories.
Production of new proteins is not required for short-term memory
but there are biochemical changes at the synapse when short term mem-
ory is formed. Serotonin produced in response to mild electrical shocks to
the tail reaches the sensory neuron and binds to its receptor on the plasma
membrane of the sensory neuron. The receptor changes shape and acti-
vates several copies of a G-protein which activates several copies of ad-
enylyl cyclase. Within a second, many cyclic adenosine monophosphate
(cAMP) second messenger molecules accumulate at the site of the sero-
tonin receptor. cAMP activates protein kinase A (PKA) by dislodging the
catalytic subunits from the inhibitory subunits. Once the catalytic PKA
subunits are released from their inhibitory subunits, local calcium ion
channels are phosphorylated as are proteins in the membranes of vesicles
responsible for permitting exocytosis of neurotransmitters (see Chapter 1).
Kandel and his collaborators verified this signal transduction pathway by
omitting the tail stimulation and merely injecting the sensory neurons
with cAMP, which caused short-term memory as measured by enhanced
gill retraction. For the first time, investigators had deduced the biochemi-
cal pathway responsible for a learned behavior in animals.
Ca2+ is required for secretion of neurotransmitters. When PKA is al-
losterically modulated by cAMP, the PKA covalently modulates the cal-
cium channels, which causes the channels to remain open longer than
normal. The longer channels are open, the more calcium floods the neu-
ron’s terminus, which increases the rate and amount of neurotransmitter
release. Similarly, PKA directly stimulates the vesicle proteins involved
in exocytosis, which further enhance neurotransmitter secretion. Short-
term memory can only persist as long as PKA is activated and the cova-
lent phosphates added to PKA’s targets remain intact. Phosphatases in
the cytoplasm will remove the activating phosphates from the calcium
channels and the vesicle proteins involved in exocytosis, returning these
two components of neurotransmitter release back to their normal activity
levels. In other words, short-term memory is enhanced neurotransmitter
release at a synapse, but the enhancement persists only as long as cAMP
and PKA remain abundant enough to overcome the local phosphatases.
Loss of short-term memory is loss of covalent modulation.
Phosphorylation by PKA is the molecular event that initiates the
conversion of short-term memory into long-term memory. One key
aspect of long-term memory formation is that the input stimulus must
be repeated, and this repetition leads to increased cAMP and conse-
quently increased amounts of activated PKA. Activated PKA not only
phosphorylates proteins involved in exocytosis of the nearby synapse and
local Ca2+ ion channels, PKA also diffuses and covalently modulates an-
other kinase called MAPK. Activated MAPK and PKA diffuse into the
nucleus and phosphorylate the regulatory protein CREB-2 and the tran-
scription factor CREB-1. Prior to being phosphorylated, CREB-2 was
bound to CREB-1, which prevented CREB-1 from forming an activated
homodimer. In other words, CREB-2 inhibits CREB-1 from becoming an
activated transcription factor. Phosphorylation of CREB-1 and CREB-2

produces opposite effects on these two nuclear proteins that have similar
names but different functions. CREB-2 acts as a threshold detector that
ensures the learning stimulus is of sufficient magnitude to overcome its
inhibitory capacity. If CREB-2 is not phosphorylated sufficiently (thresh-
old level) due to a weak input signal, then CREB-1 is prevented from
escalating the memory into long-term storage.
Once CREB-1 dimerizes, the active proteins become a potent tran-
scription factor that leads to the production of at least two new types of
proteins. C/EBP and a protease are the first two proteins produced on
the way toward long-term memory formation. The protease is translated
in the cytoplasm, and it cleaves the inhibitory subunit of PKA, liberating
more PKA. Therefore, PKA is part of a positive feedback loop that en-
hances its own production as long as sufficient serotonin stays bound to
its receptor. C/EBP is also produced in the cytoplasm, but it diffuses back
into the nucleus and functions as another transcription factor that binds
to at least two different promoters. C/EBP-responsive promoters are pres-
ent on several more genes. The proteins encoded by these “late” genes
are the molecules required for improved exocytosis of neurotransmitter.
Long-term memory formation includes additional capacity for exocy-
tosis of neurotransmitter. Memory is produced when cells sustain their
increased capacity for exocytosis in response to persistent training. Once
the level of PKA is reduced, CREB-2 resumes its inhibition of CREB-1,
and the production of new proteins for long-term memory is stopped. If
C/EBP was already produced before inhibition of CREB-1, the new pro-
teins used for exocytosis at the sensory neuron synapse will be deposited
on the plasma membrane, and long-term memory will be established.
Production of CREB-1 homodimer is the tipping point for conversion
from short- to long-term memory.
Memory involves many genes, but people with dominant phosphatase
alleles would be less likely to form long-term memories. Similarly, people
who cannot form long-term memories might have problems producing
CREB-1 homodimers, the protease, and/or C/EBP, but probably not the
exocytosis proteins, because they can form short-term memories. Con-
versely, people with photographic memories probably possess dominant
alleles of PKA or C/EBP and perhaps two recessive alleles of CREB-2,
the phosphatases, or the enzyme that destroys cAMP. Many other genes
might be involved as well, but these genes are likely candidates that would
be interesting to study the alleles in people with different capacities for
long term memory formation.
All of these discoveries by Kandel and his colleagues were impressive,
but their research presented a new problem. If memories are the result
of enhanced neurotransmitter release, how can people remember some
things but not others? In other words, if a neuron produced new proteins
for enhanced synapse formation, how does the neuron regulate which
synapse should receive the new proteins and which synapses should not?
Is an entire neuron the smallest unit of memory formation and therefore
all the synapses for a given neuron are altered simultaneously in order
to learn? To answer these questions about whether memories are stored
by an entire neuron or a single synapse, Kandel’s lab had to develop a
new experimental system. They needed to grow exactly three neurons in
a growth chamber with one sensory neuron stretched between two motor
neurons (cells A and B). Inside the growth chamber, the investigators sup-
plied a steady flow of liquid media from top left to bottom right. While
observing all three cells through a microscope, the investigators lowered
a very small glass pipet filled with a mixture of serotonin and a dye so
that they could watch the serotonin as it was added to the experiment
and drifted with the flow of liquid media away from the second neuron.
The goal of this experiment was to mimic the biochemical communica-
tion in normal learning between a serotonin neuron from the tail and the
siphon’s sensory neuron. The biologists applied five doses of serotonin
to the synapse between the sensory neuron and motor neuron A. The
investigators measured the action potentials of motor neurons A and B
after stimulating the sensory neuron just as they had done previously. In
the next experiment, they applied five doses of serotonin to the synapse
between the sensory neuron and motor neuron A as well as one dose of
serotonin to the synapse between the sensory neuron and motor neuron
B. As before, they measured the action potentials of motor neurons A and
B after stimulating only the sensory neuron.
One reason Kandel was awarded a Nobel Prize is that his experiments
were very well designed. By mixing serotonin with dye and providing a
flow of liquid over the cells, the investigators could be certain that they
had exposed only one synapse with serotonin. If they had not taken these
precautions, it would be impossible to know if the serotonin had dif-
fused from neuron A to neuron B. Learning requires multiple stimula-
tions separated by short time intervals, which is why the scientists applied
five puffs of serotonin instead of one long dose. The application of sero-
tonin only to neuron A (initiation) led to selective memory formation in
the sensory neuron as indicated by the increase in physiological response
by motor neuron A, facilitation, but not by motor neuron B when the
sensory neuron was activated. In a separate experiment, one dose of se-
rotonin on the synapse with neuron B after five doses on the synapse
with neuron A allowed the sensory neuron’s other synapse to capture a
long-term memory at synapse B that had been initiated at its synapse
with motor neuron A. The synapse with motor neuron B essentially cap-
tured a free ride from the information processing at the synapse with
motor neuron A. The enhanced action potential of neuron B after only
one serotonin dose demonstrated the sensory neuron was able to store a
new memory with less training. The five puffs of serotonin at synapse A
had biochemically altered the sensory neuron’s synapse to release more
neurotransmitter onto neuron A. When they measured motor neuron B
after stimulating only neuron A, neuron B showed no signs of enhanced
action potentials, indicating that learning and memory storage was
synapse-specific and not stored within the entire sensory neuron. How-
ever, the entire sensory neuron was primed to learn faster (facilitation)
on its second with neuron B as shown when only one dose of serotonin
was needed to alter the synapse with neuron B (capture) after already
learning at its synapse with neuron A.
Kandel and his collaborators repeated many of these Aplysia experi-
ments with mice, and they found that mammals and sea slugs share the
same molecules responsible for short- and long-term memory formation
and storage. Short-term memory is the response of one dose of serotonin,
which primarily enhances neurotransmitter release by phosphorylating
ion channels and exocytosis proteins at that synapse. Short-term memory
can lead to new physical structures that look like swellings at the synapse.
By counting the number of swellings along an axon, it is possible to es-
timate how many neurons communicate with the axon, providing the
target neuron with many opportunities for learning. Repeated doses of
serotonin leads to long-term memory formation and new synapse structures

and swellings. There are four steps from the initial stimulation of a neuron
to long-term storage of a new memory, as well as facilitation and capture.
The four steps to long-term memory formation are:
1. Serotonin modulates proteins near the input to release more neu-

rotransmitter (initiation).
2. Signal transduction leads to the activation of PKA and short-term
memory formation.
3. If PKA activation is prolonged due to repeated stimulation, MAPK
moves to the nucleus of the cell and stimulates a cascade of genes and
leads to new protein formation (facilitation).
4. PKA also marks all synapses in the sensory neuron for possible cap-
ture by making new proteins, which can lead to new physical struc-
tures and swellings at a second synapse.
Kandel’s summary included an interesting detail discovered by other

scientists—translation of mRNA can be localized to the synapse so that
the proteins do not have to travel all the way down long axons. With
the four steps listed above, a cell can learn and form a memory for the
organism. Long-term memory requires repeated exposure over many
days. Furthermore, research shows that sleep helps consolidate memories
and produces the physical structures from new protein formation.
Recent research has shown the repetitive recall of information (self-
testing) is better for retaining information than simply rereading mate-
rial. Therefore, students should quiz themselves instead of rereading their
highlighted key terms in order to retain the information in a long-term
memory. Repeated recall works well because it stimulates the same syn-
apses multiple times and leads to more protein production at the modi-
fied synapse.
Ethical, Legal, and Social Implications: Concerns

About Memory Research
In the movie The Matrix, the main character Neo is given a choice of two
pills. Take the blue pill and he will continue to live a lie, ignorant of the
past or the reality of his current state. However, the red pill will open his
mind and eyes to reality, no matter how unpleasant that may be. Today,
this choice of pills is science fiction, but will it be reality in the future?
As we learn more about how memories are formed, stored, and retrieved,
will it be possible to modify biochemical processes and alter the cellular
structure and function of memory? This may sound too futuristic, but a
group has been able to generate a memory of fear in genetically modified
mice simply by using light to open an ion channel.
Particular proteins and metabolites are the key to remembering. What
if a drug existed that would cause MAPK to be activated longer than
it would be normally and thus lead to photographic memory? Suppose
there is a drug that would selectively inactivate CREB-2, should it
be banned from schools and considered cheating the way that PEDs are
banned from athletics? Or, should a memory-enhancing medication be
viewed as the equivalent to improved equipment that produces world
record times for those who adopt the newest technology?
Consider two students: one comes from an economically disadvan-
taged family, and the other is wealthy. Both are preparing to take their
ACT tests that will help determine where they will go to college and
whether they will receive scholarships or not. The wealthy student hires
tutors, does not have to work after school, and prepares for the ACT by
taking a prep course in the evenings and weekends. The poor student has
to work 30 hours a week and does not have the money to pay for prep
courses or tutors. Instead, the poor student buys memory pills online and
takes them for several months leading up to the ACT. The two students
sit next to each other as they bubble in their answers—one feeling more
confident than the other. Weeks later, they receive their ACT scores, and
they received exactly the same perfect sore. Who should get the scholar-
ship? Has one student earned admission to the best schools and the other
cheated? What if the students reversed roles and the poor student studied
while the rich one took memory pills? Would people form a different
opinion of who should get the scholarship?
Memories fade over time as proteins at the modified synapses degrade.
As the old saying goes, “What you don’t use you lose.” To retain all of the
information learned in a class requires practice retrieving the information
to reinforce those memories. Some memories, like those formed during
a flashbulb moment of intense stress or emotion (such as, the falling of

the twin towers on September 11, 2001) persist for many years with great
clarity. Would it be ethical for scientists to develop a forgetting pill—one
that would cause synapses to degenerate and lead to a lost memory? It
might be therapeutic to erase terrible memories that persist when a person
is raped or is a witness to genocide. Or what about chemically erasing
the memory of the victim of a crime to prevent testimony during a trial
to convict the perpetrator? If such a pill were invented, could its use be
restricted to only ethical applications?
When new a technology is invented, it could be used for the benefit of
many or abused to the detriment of a few. Memory-inducing and -erasing
pills could be used for good or evil. Should this type of research be en-
couraged or forbidden? Is the basic research of Kandel the beginning of
The Matrix red versus blue memory pill application? If these pills could be
developed, assassins could learn the details of the target’s life very quickly
and then just as rapidly forget that anything happened. Is taking memory
enhancing drugs that would stimulate memories that lasted for only one
semester valuable? Students could earn a good grade but they would for-
get all that information shortly after taking the final exam. The possibility
of inventing smart pills raises interesting questions about how we measure
intelligence and who we consider to be smart. If a person has a photo-
graphic memory and can remember everything they have seen but cannot
imagine new situations or synthesize data to produce a new conclusion, is
this person smart? The movie Limitless in one person’s vision of what such
a pill might be able to do, both good and bad.
Ethical dilemmas come with new knowledge. Not long ago, it seemed
crazy to think humans could clone animals or grow human organs in the
lab. In more recent times, it seemed crazy to imagine having the world’s
libraries at one’s disposal in a handheld device. Today, memory and for-
getting pills seem outlandish, but they could become reality. Scientists
cannot be held responsible for the actions taken by others. But a new
chemical alters memory in mice, is the scientist really innocence if some-
one develops a similar pill for humans and uses the pills for evil purposes?
Contrary to the way scientists are portrayed in the media, they live in our
shared society and must decide how they will spend their talents and the
resources entrusted to them.
Bibliography
Costa-Mattioli M. Eppendorf winner: switching memories ON and OFF.
Science 322(5903):874–875, 2008.
Kandel ER. The molecular biology of memory storage: a dialogue be-
tween genes and synapses. Science 294(5544):1030–1038, 2001.
Shepherd GM, Raastad M, Andersen P. General and variable features of
varicosity spacing along unmyelinated axons in the hippocampus and
cerebellum. Proc Natl Acad Sci 99(9):6340–6345, 2002.
Conclusion
Not all cells rely on electric current for their primary function, but all
cells have a membrane potential. Neurons consume energy to generate
an ion gradient, which produces a membrane potential due to the overall
negative charge inside cells. Ions rush across the membrane, and an action
potential can sweep down the length of a cell in milliseconds, even if the
cell is 10 feet long. Due to the speed of electrical communication inside
cells, diffusion does not constrain the length of neurons. Like neurons,
muscle cells use Ca2+, Na+, and K+ ion gradients to generate electrical
and chemical waves of communication. Skeletal muscles are composed
of many, many fused cells that coordinate their production of actin and
myosin so that muscles can contract. Muscle cells have the specialized SR
structure that facilitates fast and uniform distribution of Ca2+ ions.
Neurons can form memories by altering the structures of their synapses.
Altered synapses release more neurotransmitter, which is the molecular
mechanism that allows organisms to learn and form memories.
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Glossary
acetylcholine. neurotransmitter secreted by neuron to stimulate a muscle to contract.
actin. actin monomers form long twisted polymer rods that appear lighter in
micrographs of sarcomeres.
action potential. action potential is a moving wave of electrical current traveling
one direction down an axon.
allosterically modulated. when a molecule or element binds non-covalently to a
protein and alters the protein’s shape and function.
Aplysia. genus name of the sea slug used by Eric Kandel to study how memories
are formed.
cAMP. cyclic AMP, signaling molecule made by adenylyl cyclase from ATP substrate.
capture. when a synapse deposits new proteins to enhance its response to a stimulus.
covalent modulation. when a molecule (often a phosphate) binds covalently to a
protein and alters the protein’s shape and function.
cross sections. cross sections are cut perpendicular to the long axis of a structure.
depolarized. depolarized membranes have less separation of charges than a
polarized membrane at resting potential.
dimerizes. when two monomer proteins physically interact and are bound to each other.
exocytosis. exocytosis is the secretion of cellular products when a vesicle fuses
with the plasma membrane.
facilitation. a neuron’s ability to release more neurotransmitter with the same stimulus.
G-protein. signaling molecule that carries the message of a ligand binding to its
receptor into the cytoplasm.
homodimer. two identical copies of a molecule form a dimer.
hyperplasia. hyperplasia is the proliferation, or division, of cells.
hypertrophy. hypertrophy occurs when individual cells grow in size.
initiation. the training, or education, of a neuron for memory formation.
ion channels. membrane proteins that allow ions to pass through their central pore
and move from an area of high concentration to an area of lower concentration.
ligand-gated. it describes one way that an ion channel can go from closed to open
when a ligand binds to the channel to gate, or open, the channel.
long-term memory. related to this book, it is the sea slug remembering for more
than one day.
motor neurons. motor neurons convey electrical impulses from the nervous
system to a muscle or gland.
myelin. the white colored insulation around a neuron, caused by a Schwann cell
wrapping its membrane around the axon.
myelinated. a neuron wrapped by myelin.
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48 GLOSSARY
myosin. myosin molecules are longer and bundle together to form thicker
myosin rods in micrographs of sarcomeres.
Na1/K1 pumps. one of the proteins that contributes to membrane potential by
pumping 3 sodium ions out and 2 potassium ions in for every ATP consumed.
nodes of Ranvier. nodes of Ranvier are 1 µm gaps between Schwann cells that
permit faster electrical conductance in neurons.
patch clamp. experimental method that allows investigators measure the activity
of single ion channels.
performance-enhancing drugs. often steroids, this pharmaceuticals are used
illegally by some athletes to build bigger muscles.
refractory period. refractory period is when ion channels cannot reopen a
second time until they have rested for some time.
resting membrane potential. the difference in electrical charge on two sides of a
membrane when a neuron or muscle cell is not active.
sarcomere. a sarcomere is composed of overlapping rods of myosin and actin
proteins and are responsible for muscle cell contraction.
sarcoplasmic reticulum. it is found only in skeletal muscles, this specialized form
of the endoplasmic reticulum stores calcium to regulate muscle contraction and
communicates closely with the T-tubules.
secretory vesicles. small membrane spheres that contain molecules to be released
by the cell, such as neurotransmitters by a neuron.
sensory neurons. sensory neurons receive information and communicate with
others cells.
serotonin. serotonin is one example of a neurotransmitter that can enhance or
reduce the function of the recipient cell, depending on the receiving cell type.
short-term memory. related to this book, it is the sea slug remembering for only
a few hours, less than one day.
skeletal muscle. muscles that are connected to bones and are responsible for most
of of animal body movement.
striated. skeletal and cardiac muscles are striated, meaning you can see stripes in
them when examined through a microscope.
synapse. a very small separation between a neuron and the cell it is secreting onto,
such as a muscle or another neuron.
transmembrane. proteins that span the membrane (one or more times) of a cell
and are embedded in the membrane.
tropomyosin. long rod protein that binds to actin polymers and blocks myosin
binding site.
troponin. calcium sensitive protein that allosterically modulates tropomyosin to
regulate muscle contraction.
T-tubules. it is a specialized membrane system consisting of plasma membrane
“tunnels” that carry the depolarization from the surface of the skeletal muscle
cell into the interior of the cell to expedite electrical signal transduction to
the sarcoplasmic reticulum.
voltage-gated. it describes one way that an ion channel can go from closed to
open when membrane depolarization near the channel causes it to gate, or open.
Index
Actinpolymers, 24 International Olympic Committee
Action potential, 8 (IOC), 30
in neurons, 14
prevent an echo of, 11 Kandel, Eric, 33
protential response of, 15
Active transporter, 2 Ligand-gated ion channels, 8
Adenosine triphosphate (ATP), 2 to initiate electrical
to adenosine diphosphate (ADP), 3 communication, 16
binds to myosin, 25 Lighter protein rods, 23–24
myosin consumption, 24–25 Long-term memory, 34
Aplysia, 33–34 formation of, 38
electrical shocks, purpose of, 34 key aspect of, 37
gill retraction in, 35 steps to, 41
neuron L7, stimulation of, 34–35
neurons responsibility, 34 MAPK, 37
Memories
C/EBP, 38 people with photographic, 38–39
Ca2+-binding protein, 17 require new proteins in neurons,
Cardiac muscle, 21 33–43
Cellular current, measurement of, 7 Motor neurons, 22
Chemical communication, 4 versus sensory neurons, 34
Conscious contraction versus reflexive mRNA, translation of, 41
muscle movement, 35 Muscles
Covalent modulation, 5 anatomy and structure, 21
CREB-1, 37–38 ATP in, 25–26
CREB-2, 37–38 cell, longitudinal view of, 23
Cyclic adenosine monophosphate contraction and growth, 21–31
(cAMP), 36 experiments for bigger muscle
growth, 28
Depolarization, 12 microscopic images of, 22–23
neuron communication, 22
Exocytosis, 16–17 number of nuclei in, 22
of neurotransmitter, 38 performance-enhancing drugs
(PEDs), use of, 29–31
G-protein, 36 sarcomeres, 22
Gastrocnemius, 28, 29 T-tubules in, 26–27
Gill retractions, 35 vertebrates, types of, 21–22
neural circuit connecting tail Myelin sheath, 14
shocks, 36 electron micrographs of, 14–15
Myelinated axons, 14
Homodimer, 38 Myosinpolymers, 24–25
Hyperplasia, 27–28 cycle, 25
Hypertrophy. See Hyperplasia rod polymers, 25
50 INDEX
Na+/K+ pump, 3–4 Refractory period, 11

chemical activity of, 4–5 Regulatory protein, 37
Neurons Repolarization, 12
benefit of myelin, 15 Resting membrane potential, 4
use electrical communication, 4, 14
function of, 13 Sarcomere, 22
membrane proteins for, 12–13 composition of, 23–24
memories require new proteins membrane network surrounding, 27
in, 33–43 Sarcoplasmic reticulum (SR), 26–27
movement of Ca2+ ions, 16–17 Schwann cells, 14
to muscle cells, 4 Secretory vesicles, 16–17
Na+/K+ pump, 3–4 Sensory neurons
at neuromuscular junction, 1 versus motor neurons, 34
neurotransmitter receptor, 6–7 serotonin neuron
potential energy, 5–6 communication, 35
receive and send information, 1–18 Serotonin
repolarization of, 11 neuron communication, 35
resting state of a neuron, 1–2 neuron from tail and siphon’s
secretory vesicles, 17–18 sensory neuron experiment,
stimulation and measurement of 39–40
electrical current in, 7–8 Short-term memory, 34Short-term
with threshold depolarization, 8 memory, 34, 35–36, 40–41
Nodes of Ranvier, 15 Skeletal muscle, 21
contraction of, 22, 26, 35
Patch clamp method, 13 Smooth muscle, 21
Performance-enhancing drugs Sodium ion channel, structure and
(PEDs), 29–31 function, 6
Phosphorylation by PKA, Steroid injections, 30
37–38
Plantaris, 28 Testosterone, 29–30
Potent transcription factor, 38 Thicker dark protein rods, 23
Protease, 38 Transmembrane domains, 5
Protein kinase A (PKA), 36–37 Tropomyosin, 26
phosphorylation by, 37–38 Troponin, 25, 26
Proteins T-tubules, 26
four types of, 13
memory research, 41–43 Vertebrates, types of, 21
in muscles, 28 Vesicle proteins, 37
in neurons, memories require Voltage-gated ion channel, 8–9
new, 33–41 propagate signal down, 16
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Neurons and Muscles

A. Malcolm Campbell, PhD

Neurons and Muscles

All rights reserved. No part of this publication may be reproduced, stored

First published in 2016 by

ISBN-13: 978-1-94474-908-8 (print)

Momentum Press Biology Collection

Cover and interior design by S4Carlisle Publishing Services Private Ltd.,

Printed in the United States of America

Neurons Receive and Send

Figure 1 Neurons use chemical and electrical signals to communicate

maintain this unbalanced ionic state with a higher concentration of Na+

Table 1 Concentration of ions inside and outside animal cells.

Figure 2 Primary and quaternary structure of a Na+/K+ pump. A,

Neurons Receive and Send Information 5

Figure 3 Chemical activity of the Na+/K+ pump. Diagram of the

phosphorylated, the covalently modulated pump has a shape change in the

particles. In Figure 1, the upper chemical communication box highlights

A top view B side view

Figure 4 Gated sodium ion channel structure and function. A, Channel

to flow down their chemical and electrical concentration gradients into

Figure 5 Stimulation and measurement of electrical current in

is easily controlled. Figure 5B shows the averaged results from repeated

Figure 6 Depolarization at one point in time. A neuron was

measure #1 measure #2 measure #3

Figure 7 Depolarization over time. A neuron was stimulated (top

open. As with any form of diffusion, intracellular sodium ions spread to

cytoplasm cytoplasm cytoplasm

A after depolarization B depolarized C shortly after depolarization

Figure 8 Neuron repolarization. A, Once closed, a voltage-gated

Therefore, the neuron needs an equally fast mechanism to return the

axon plasma membrane

Figure 9 Patch clamp method measures single channel activity. Pipet

channels and voltage-gated K+ channels are approximately equal. They

If three ion channels were independently stimulated by a defined elec-

axon of nerve cell

myelin from Schwann cell

Figure 10 Myelinated axons conduct electricity faster than non-

plasma membrane wrapping produces an insulator of sufficient thickness

The nerve impulse began with a chemical signal that activated

the termini of axons, neurons accumulate secretory vesicles that contain

Long SB, Campbell EB, MacKinnon R. Crystal structure of a mamma-

Muscles Contract and

Vertebrates have three types of muscle cells: smooth, cardiac, and

cardiac muscle cells

skeletal muscle cells

smooth muscle cells

Figure 11 Muscle anatomy and structure in three types of vertebrate

longitudinal section 3D perspective cross sections

Figure 12 Visualizing 3D objects when cut at different angles. A

anchored ends free ends of

Figure 13 Actin and myosin interactions provide contractile function.

Muscles Contract and Grow Bigger 25

actin troponin tropomyosin

Figure 14 Troponin and tropomyosin regulate muscle contraction.

and tropomyosin (Figure 14). Tropomyosin binds to actin and blocks

Figure 15 Membrane network surrounding sarcomeres. Diagram

That’s why skeletal muscles have so many nuclei in a shared cytoplasm.

plantaris dry mass (mg ± 1 stdev)

Figure 16 Effect of removal of the left gastrocnemius muscle on the

Ethical, Legal, and Social Implications: Use of

30 NEURONS AND MUSCLES

growth hormone produced by men and women. Because testosterone is