Physiology Exam 1 Lecture Objectives

Membranes:
1. Role of membrane in maintaining composition of intracellular fluid (Homoeostasis)
a. Does so by compartmentalization
b. Bilayer is impermeable to hydrophilic substances (dissolves well in water)
i. Permeable to gases and lipid soluble molecules
ii. All else requires special transporter
iii. Thus membrane is semi-permeable
c. K+ is major ion in cytoplasm
d. Na2+ is major ion in extracellular fluid

2. Membranes main functions

a. Physical boundary of cell and intracellular organelles
b. Compartmentalization (separation)
c. Transport
i. Physical matter
ii. Information (communication)
1. Across Membrane (Signal Transduction) - Intracellular
2. Along Membrane (Propagation) Intercellular
a. Excitability
3. Main function of the main constituents
a. Glycocalyx (cell coat): carb of glycolipid and glycoproteins
i. Protection
ii. Lubrication
iii. Cell/cell recognition (ex: blood groups_
b. Membrane Proper: lipids and proteins
c. Cell Cortex (part of cytoskeleton): proteins
i. Cortical actin
ii. Integrity, flexibility, control of membrane proteins
iii. Spectrin/actin cortex keeps integrity of RBC
4. Composition of membrane lipids:
a. Phospholipids:
i. Form bilayer due to phospholipid polarity
ii. Move freely within plane of bilayer (lateral movement) fluidity

iii. Individual phospholipids can rotate (rotational movement)

iv. Bilayer held by hydrophobic interactions no transverse movement
b. Cholesterol:
i. 50% of lipids in membrane
ii. Enhances fluidity by preventing phospholipids from packing closely
iii. Hydrophobic + Hydrophilic areas like phospholipid bilayer
iv. High temp environment more cholesterol in membrane
v. Enhances impermeability by filling gaps in phospholipids
vi. Reduces cells ability to lyse by making it more flexible
c. Glycolipids:
i. Only in plasma membrane
ii. Sugar chain (15 polar units) covalently bonded to phospholipid
iii. Always towards outside of cell membrane
iv. Cell recognitions
v. Cell receptor
vi. Control/regulates function of membrane proteins
d. Sphingolipids
i. Signaling molecule
ii. Makes myelin
iii. Based on sphingosine + fatty acid
iv. Has double bond near polar amine end of sphingosine
v. Hydrophobic + Hydrophilic areas resembles phospholipids

5. Role of hydrophilic and hydrophobic interactions

a. Hydrophobic Molecules: stick together in water to cause less disruption
i. Ex: lipids form droplets in cell cytoplasm
b. Hydrophilic Molecules: surrounded by shell of water
6. Role of hydrophilic and hydrophobic interactions among molecules in the self-assembly
of membrane bilayer
a. Amphiphilicity: hydrophilic head and hydrophobic tail form micelles in water
b. Bilayer formed by amphipathic lipids
i. Core is very hydrophobic water cannot pass through
ii. Held together by hydrophobic interactions

Diffusion and Osmolarity:

1. Various expressions of concentration:

2. Molar expression of concentration:

M =
1 mole = 6 1023 molecules (Avogadros number)

3. Factors that determine direction of diffusion:

a. Concentration of particles
b. Barrier has to be permeable

4. Main factors that determine Flux and express them quantitatively in Ficks law:

a. Flux: rate of diffusion ( )

b. Factors that determine flux:
i. Membrane Permeability
ii. Size of particle (heaver = slower)
c. Ficks Law: flux is proportional to concentration difference
i. Higher difference = higher flux

5. Know membrane and solute properties that determine permeability for diffusion:
a. Permeability:
i. Proportionality constant between flux and concentration gradient
ii. Differs for different membrane and substances
b. Higher Permeability:
i. Membranes: higher area and thinness
ii. Solutes: uncharged, small, and large partition coefficient
6. Distinguish solutes that permeate through bilayer and those that permeate through
transport proteins:
a. Solutes through Bilayer:
i. Gases
ii. Small, non-ionic
iii. Fat-soluble
iv. Substances w/ high partition coefficient (fat soluble)
1. Codeine
2. Xylocaine/Novocain
b. Solutes through Transport Proteins:
i. Large, polar
7. Apply above rules to diffusion of water (osmosis)
a. Can pass through water-permeable membrane
b. Occurs through aquaporins
c. Water from high to low concentration
d. Water stops moving when fluxes from both sides are equal
e. Can be stopped by applying hydrostatic pressure

8. Osmolarity and osmotic pressure:

a. Osmolarity: total concentration of particles of solutes regardless of chemical nature
i. ONLY number of impermeable particles
b. Osmotic Pressure: caused by solute molecules
i. Use vant Hoffs Law:

ii. Equal to pressure of solutes

iii. Osmotic Pressure increases as solute concentration increases
1. Ex: 1 M CaCl2 is higher than 1 M KCl
iv. No hydrostatic pressure difference = sum of osmotic pressures off solutes is 0

Ions: Voltages
1. Measurement of membrane potential
a. Use voltmeter to measure voltage difference Vi-Ve
b. Neurons: -70mV
c. Skeletal Muscles: -90mV
2. Requirements for existence of electrical forces
a. Whenever excess charge of one sign is in one region
b. Opposite charges attract, remaining charged particles allow for electrical potential
difference
3. Definition of electrical potential and electrical potential difference
a. Electrical Potential: potential energy of the unit of charge
b. Electrical Potential Difference: excess charges cause difference
i. Has ability to do work
4. Capacitance
a. Proportionality constant between charge and membrane potential
b. Capacitance = Charge/Potential
c. Thicker membrane = more work = more potential = less capacitance
i. Key for why nerves are myelinated
5. Electrochemical equilibrium for one ion
a. Assume K+ and Cl- on both sides of membrane only permeable to K+
b. There is more K+ on left side thus due to chemical gradient it will diffuse to the right
until in chemical equilibrium
c. This buildup causes an electrical gradient with + signs built up on the right of the
membrane and signs on the left
d. Due to the attraction of opposite charges, the K+ will want to go back to the left side
of the membrane and will do so. This will then cause a shift in the concentration
gradient and cause K+ to want to go back to the right.
e. Both an electrical and chemical gradient will oppose one another causing an
electrochemical equilibrium
f. *Water only depends on concentration gradient not membrane potential
6. Application of Nernst equation to specific examples with the 4 main ions
a. Only Cl- is at equilibrium b/c it is at -70mV

7. Application of Nernsts equation to nerve cell at rest, difference between resting

potential and equilibrium potential of ions
a. Equilibrium Potential: defined per ion (property of ion not membrane)
b. Resting Potential: is for membrane and takes into account all ions involved

c. If membrane only permeable to K+, Ek = Vm

d. Resting potential always more positive than E k because membrane is also permeable
to Na+ and Cle. Each permeable ion drives membrane potential towards its equilibrium potential
i. Ions with greatest permeability will make greatest contribution to resting
membrane potential
ii. At rest, nerve membrane is more permeable to K+ than to Na+
8. Electric potential difference generated when multiple permeant ions are present at
unequal concentrations. GHK equation (Goldman-Hodgkin-Katz)

9. Electrochemical potential difference (EPD)

a. Difference between actual transmembrane potential (V m) and equilibrium potential of
ion
i. Ex: Ek = -90, Vm = -70 -70 - -90 = +20 (EPD) K+ will move out
b. Cl- acts as stabilizer for membrane potential since E cl = -70 just like Vm

Transporters: Pumps and Carriers:

1. The crucial role of the Na+ pump in maintaining resting potential
a. Na/K pump maintains concentration differences that originate the resting potential
by working against the passive fluxes of Na and K
b. 2 K in / 3 Na out for each ATP hydrolyzed
c. Causes accumulation of extracellular positive charge (electrogenic)
2. Classification of transport mechanisms: (energy consumption + structure)
a. Passive:
i. Simple (channel protein) substances move right through membrane
ii. Facilitated (transporter protein)
iii. Driven ONLY by electrochemical potential difference (EPD)
b. Active (transporter protein)

3. Simple diffusion vs. carrier-facilitated diffusion

a. Diffusion can be either simple or carrier mediated (facilitated)
b. Facilitated uses channels or carriers
c. Look at chart above
d. 3 Main differences:
i. Saturation
ii. Specificity
iii. Competition
e. Facilitated diffusion only has certain amount of binding sites so as
concentration increases the flux will not be linear as in Ficks law,
but it will level off

4. Examples of single carriers with a single substrate

a. Primary active transport
5. Main pumps (primary active carriers). Stoichiometry of plasmalemmal Na-K pump
a. Primary active carriers:
i. Protein molecule (pump) associate (couple) the transfer of solute across
membrane with use of ATP
ii. Ex:
1. Na/K pump in plasma membrane
2. Ca pump in endoplasmic reticulum
3. H+ pump for HCl secretion in stomach
6. Coupled carriers: cotransporters and counter-transporters:
a. Transfers solute without ATP, but uses energy stored in electrochemical potential
difference
b. Both (secondary active transporters) always use Na
c. Exchanger = Counter-transporter (bubblegum machine)
i. Na-Ca exchanger 3 Na goes inside with gradient, 1 Ca outside against
d. Cotransporter:
i. Na/glucose Na goes along gradient, Glucose against
7. General organization of transporting epithelia:
a. Occurs in exocrine glands and lumen of absorptive organs
b. Single layer of cells does the transport
c. Main thing: polarity
i. Epithelia has 2 sides apical/lumenal and basolateral (interstitial)
d. Apical (lumen) and basolateral (blood) sides are different in composition,
meaning transport molecules
i. Difference maintained by tight junctions
e. Basolateral: rich in Na/K pumps maintains electrochemical gradient for Na
8. Absorption of glucose in small intestine
a. Glucose concentration must be high for it to go into blood
b. Glucose and Na move together on apical side
c. Glucose goes into cell
d. Interstitial side has glucose carrier to move glucose down gradient
9. Reabsorption of Na+ and fluid in intestine and absorptive epithelia
a. Na moves from apical to interstitial side water will follow
i. Na goes through epithelial Na channel (EnaC or Amiloride-sensitive
channel)
ii. Channels of these increased by aldosterone
iii. Channels different than voltage-gated
b. At basolateral side, there is Na-K pump
c. 3 Na out, 2 K in

10. Secretion of Cl- and fluid in secretory epithelia

a. Ex: sweat gland
b. CFTR is Cl- channel on apical end
i. In cystic fibrosis: channel doesnt work thick mucus secreted
c. Cl- moves from interstitial to apical
d. Basolateral end:
i. Cotransporter Na, K, 2Cl together into cell from interstitial end
e. Apical end:
i. Na and H2O go down gradients in through tight junction both secreted
at apical end
ii. Cl secreted through CFTR

Transporters: Channels
1. Main Characteristics of ion channels: selectivity, conductance, gating

a.
b.
c.
d.
e.

Total current through 1 type of channel is sum of single channel currents

Amplitude of ionic current independent of opening/closing kinetics of channel
Open Probability in formula is a kinetic characteristic
Current depends on voltage and ion concentration
Driving force of ions through open channel = EPD
i. High driving force = lots of current
ii. Driving force at 0 = equilibrium
f. Condunctance high = large current = steeper curve
g. Po is function of voltage gates open/close depending on voltage

2. Concepts of sensors, gates, selectivity filter

a. Gates
i. Channels are either on or off, no halfway
ii. Gates represent movement of proteins that permit flux
iii. Movement of gates are too fast to observe
b. Gating Mechanisms:
i. Open:
1. Contribute to resting potential
2. Always open
3. Usually K+
ii. Voltage gated:
1. Responds to change in membrane potential

iii. Extracellular Ligand-Gated:

1. Responds to extracellular neurotransmitters (AcH, glycine)
iv. Intracellular Ligand-Gated
1. Responds to intracellular signal transduction events
2. Ca channels that sense ATP
3. Regulation of insulin Ca channels close when sugar high
v. Mechano-sensitive:
1. responds to mechanical stress
2. membrane surface tension
c. Selectivity Filter:
i. Does not depend on flux or gating mechanisms (open probability)
ii. Responsible for how much and what ions move in after gate opens
iii. Can determine by looking at graph
1. K+ has eq. potential at -90mV (Case 1)
2. Na+ at +60 (Case 3)
3. Not selective (Case 2)

d. Sensors:
i. When depolarized, inside is charged more positively
ii. Gating particle (positively charged) moves away from positive interior and
pulls the positive ions through the gate
3. Main properties of voltage-gated Na and K channels that underlie action potential
a. K Channel:
i. Activation gate is slow while Na activation fast, inactivation slow
ii. Activation gate is so slow that inactivation gate can be disregarded since
activation gate is the limiting factor
b. Na Channel:
i. Inactivation on inside and activation gate inside channel
ii. At rest:
1. Activation gate closed
2. Inactivation gate open
iii. First 2-5 ms. of Depolarization:
1. Both gates open
iv. Prolonged Depolarization:
1. Activation gate open
2. Inactivation gate closed
v. Back to negative membrane potential:

1. Both gates closed (inactivation gate lags)

vi. After recovery back to resting membrane potential:
1. Activation gate closed
2. Inactivation gate open
4. Stead-state activation and inactivation gates in voltage-gated Na channels
a. Inactivation Curve:
i. Neg. voltage = inactivation gate open
ii. Pos. voltage = closed
b. Activation Curve:
i. Neg. voltage = closed
ii. Pos. voltage = open
c. Both gates open at same time is small fraction of time

5. Molecular topology of voltage-gated channels and determinants of the voltage sensors,

gates, and the selectivity filter in voltage-gated K channels
a. Voltage-Gated Channels
i. Created by 1 polypeptide
ii. 3-4 subunits
iii. Pore-forming subunit = 1
iv. Each subunit has domain (1-6 parts + loop pattern)
v. Loop is between 5 and 6 is selectivity filter
vi. 4 = voltage sensor, gating portion
b. In potassium channels it is very similar
i. ONLY 1 domain, tetramer
ii. Same complexity as Na channel, but smaller
iii. 1-6 parts are -helices
iv. Part 4:
1. Lysine (K) and Arginine (R) come every 23 amino acids, 5-7 per helix
c. KcsA K+ Channel:
i. Two transmembrane segments with carbonyl
oxygens
ii. Side chains pulled apart to give exact match for K+
1. Highly selective
2. Highly conductive

6. Examples of channelopatheis diseases due to alterations of channels

a. Results from one amino acid alteration (point mutation)
b. Paramyotonia congenita
c. Hyperkalemic Periodic Paralysis
d. Potassium Aggravated Myotonia
e. All result in stiffness, followed by weakness of muscle
7. Na channel myotonias:
a. Transmitted as dominant trait
b. Caused by a point mutation in gene
c. Associated with change in function of Na channel inactivation gate
d. Activation gate normal
e. Stiffness followed by weakness
f. Multiple response to single stimulus
g. Worsened by exercise, cooling, potassium rich foods
8. Stabilizing role of Cl channels and causes of myotonia congenital
a. Cl channel myotonias aka myotonia congenital is associated with reduced number
of functional Cl channels in muscle membrane
b. At rest Cl ions are at equilibrium no passive flux
c. Cl ions exerts negative feedback on membrane potential, making it stable
i. Will not allow membrane to respond to action potential to small
perturbations of resting potential
d. In myotonia, Cl ionas are greatly reduced membrane less stable
e. Only affects muscles NOT heart
f. Treatment:
i. Exercise
ii. Drugs that inhibit Na+ channels (quinine, phenytoine)

Signal Transduction
1. Distinguish between endocrine, neurocrine, paracrine, and autocrine mechanisms of
extracellular signaling based on site of hormone release and pathway to target tissue:
a. Neurocine:
i. Like telephone wire direct = fast
ii. Problem is with many cells = hard to coordinate
iii. Uses neurons
iv. Synaptic signaling with neurotransmitters at synaptic cleft
v. Signals: AcH, glutamate
b. Endocrine:
i. Chemical signals
ii. Endocrine cells release hormones into blood to target cells with correct
receptor
iii. Signals: insulin, epinephrine
c. Paracrine: (local)
i. Nearby cells talking to each other (same cell in same tissue)
ii. Signals: cytokines, histamines, prostaglandins
d. Autocrine: (local)
i. Releases messages that that it reads itself
ii. immune signaling
iii. Signals: cytokines, histamines, prostaglandins
e. Juxtacrine:
i. Signaling chemical does not leave cell surface
ii. Signals by plasma membrane-attached proteins
2. Concepts of cell surface hormone receptors and signal transduction through second
messengers. Explain how/why these differ for cell-permeant hormones (steroids)
a. Cell surface hormone receptors:
i. On plasma membrane of cell surface and receives hormone
ii. Signal relayed to intracellular targets by signal transduction
iii. Long term effects alterations in gene expression
iv. Short term effects altering protein function, protein phosphorylation
b. Cell-permeant hormones:
i. Lipophilic so it can pass through membrane
ii. Goes straight to nucleus to regulate gene
c. Both ways can change cell behavior:
i. Altering protein function (intracellular signaling pathway)
ii. Altering protein synthesis (gene expression)
3. Describe basic signaling mechanisms used by nuclear receptors, receptor tyrosine
kinases, and G-protein coupled receptors. Classify which type of hormone signal utilize
these signal pathways.
a. Nuclear Receptors:
i. Transcription activating domain
ii. DNA-binding domain

iii. Ligand binding domain

iv. Inactive form:
1. Inhibitory protein attached to COOH
v. Active Form:
1. Inhibitory protein falls off
2. Ligand surrounded by ligand binding domain + COOH
3. Coactivator proteins attach
4. DNA binding domain binds to DNA at receptor binding element
vi. Ex: AcH
b. Tyrosine Kinase Receptors:
i. Outside: binding site for hormone
ii. Inside: enzymatic activity
iii. Receptor dimerizes to get active catalytic subunit
1. Kinase activity occurs on dimers on cytosolic side
2. Autophosphorylation occurs by taking P from ATP
iv. Ex: EGF and insulin receptors
c. GPCR:
i. Least active receptor
ii. 3 subunits
iii. Regulates cell function using secondary messengers
iv. Ex: Glucagon receptors
4. Be familiar with components of G-protein signal transduction pathway. Summarize key
steps in process by which pathway is turned off and on
a. Signal molecule attaches to GPCR
b. G-protein activated part attaches GTP and dissociates
c. -part interacts activates effector protein (some cases adenylyl cyclase)
d. To turn off: GTP is hydrolyzed to GDP dissociates from effector
5. Diagram key steps of second messenger system involving adenylyl cyclase, generation of
cAMP and activation of cAMP-dependent protein kinase

a. phosphate put on hydroxyl side of side chain

b. Phosphorylation by protein kinases changes activity of proteins
6. Describe second messenger system involving phospholipase C and generation of
Diacylglycerol and IP3. Recognize role of calcium in intracellular signaling.
a. DAG: activates PKC
b. IP3: increases cytosolic Ca2+
c. Phospholipase C acts on lipids (PIP2 phosphatidylinositol 4,5 bisphosphate)
i. Cleaves it into DAG and IP3

7. Concepts and mechanisms involved in covalent modification of proteins by protein

kinases. Understand how protein phosphatases act to reverse protein phosphorylation
and maintain dynamic balance with kinases.
a. Each protein kinase has specific activator (ex: cAMP) and distinct substrate
requirements for particular amino acid sequences
b. Most kinases can phosphorylate multiple substrate proteins
c. Regulatory system:
i. Phosphoprotein phosphatases controls phosphorylation state
ii. Steady-state balance determined by balance of kinase and phosphatase
iii. Kinase = phosphorylates
iv. Phosphatases: de-phosphorylates

G Protein Activators:

Gs:
o Norepinephrine
o Epinephrine
o Glucagon
Gi:
o Norepinephrine
o Prostaglandins
o Opiates
Gq:
o Ach
o Epinephrine

Excitation: Action Potential

1. Main characteristics and properties of action potentials in nerves/muscles
a. All or none
b. Non-decremental
c. Unidirectional
d. Both Passive and Active processes:
i. Passive: local currents
ii. Active: regeneration of action potential involving Na+ channels
e. Contains overshoot in depolarization
i. Time during which interior of cell is positive
ii. Magnitude of max. positivity
f. Muscles:
i. more neg. resting potential (-90)
ii. depolarizing afterpotential even though it is neg. still called depolarizing
because it is still relatively more positive to resting potential
g. Neurons:
i. about -70
ii. hyperpolarization afterpotential
h. Cardiac cells: AP lasts 200ms
2. Common property of all stimuli for action potentials
a. All stimuli require injecting positive electrical current
3. Local responses caused in cells by an injection of current
a. Local responses caused if stimuli only reaches subthreshold
b. NOT all or none
c. Can be decremental
d. Can propagate in any direction
e. Defined by passive electrical properties
4. Ion movements during depolarizing and repolarizing phases of action potential
a. Depolarization:
i. Na+ moves into cell
ii. Cell becomes more positive
iii. EPD becomes more negative
iv. Amount depolarized depends on eq potential goes until EPD = 0
b. Repolarizing:
i. K+ moves out of cell
ii. Large EPD for K+ once Na+ at equilibrium
5. Role of feedback (pos. and neg.) in producing Action potential
a. Depolarization = positive feedback (fast, rapid)
i. Stimulus causes depolarization locally
ii. Na+ channels eventually open causes further depolarization
b. Repolarization = negative feedback (stabilizes)

i. At some point during depolarization, permeability to K+ increases while

permeability to Na+ decreases reduced depolarization
6. After-potential and refractoriness
a. Absolute refractory:
i. No stimulus can cause AP
ii. Due to Na channel inactivation
b. Relative refractory:
i. Na+ channels have recovered
ii. No AP can be produced b/c it is below resting potential
iii. Na channels reopen, but more K channels are open and K channels are slow to
close hyperpolarization
7. Role of Ca2+ in ventricular muscle AP
a. Allows AP to be prolonged
b. Has a characteristic plateau
c. Ca2+ channels are slow to open and close longer AP

Propagation of Excitation
1. Electrical records obtained with intracellular and extracellular electrodes
a. Extracellular electrodes:
i. Used to measure propagation of AP down axon
ii. Pair of electrodes places on axon on various locations records propagation
iii. 2 characteristics:
1. 2 or more phases
2. Smaller amplitude cell membrane is only separator of charge from
electrodes, thus less potential less potential difference
2. Spatial propagation as a consequence of regenerative current injection
a. Stimulus caused by injections cause local depolarization at first
b. Further injection causes AP which results in spatial propagation
3. Importance of refractory periods for unidirectional propagation
a. So it will not go bidirectional cannot go backwards, only away from injection site
b. Because of refractory period, previously stimulated regions cannot be excited again
and thus can only go unidirectional
4. Spatial factors affecting propagation. Relationship between space constant and speed of
propagation
a. Length Constant depends on
i. Specific Resistance of Resting Membrane (Rm)
1. Greater resistance (fewer open channels) = greater constant
ii. Longitudinal, internal resistance (axon diameter) (Ri)
1. Smaller internal resistance (greater diameter) = greater constant
iii. Greater constant = faster propagation

5. Temporal factors affecting propagation

a. Density of Na channels
i. higher density = faster propagation
ii. positive feedback kicks in faster
b. Specific membrane capacitance (membrane thickness)
i. Lower (thick membrane) = faster

ii. Higher = more current needed to reach threshold = slower propagation

6. Myelin. Structural differences between myelinated and non-myelinated axons that
determine the greater speed of propagation in myelinated axons
a. Myelin in PNS by Schwann cells
b. Fastest conducting nerve fibers = myelinated
c. Myelinated structure:
i. Tight, insulating cuff
ii. Leaves open narrow regions = nodes of Ranvier
iii. Few channels in membrane under myelin
iv. Na channels concentrated near nodes of Ranvier = faster propagation
d. Factors increasing propagation speed in myelinated axon:
i. Spatial:
1. Few channels under myelin (high Rm)
2. Large diameter (low Ri)
ii. Temporal:
1. Thick membrane (low Cm)
2. High density of Na channel in nodes
7. Saltatory conduction
a. Due to fast conduction is discontinuous = action potential jumps node to node
b. Na channels only at nodes so allows AP to jump
c. Efficient since it saves internode from outflow of K+ since only nodes have to
repolarize, not the entire axon. Thus, it saves the axon from having to repolarize
throughout the whole axon, but instead just at the nodes.
8. Classification of peripheral nerve fibers

9. Safety factor for conduction

a. Safety factor: amount of nodes one node can activate before losing action potential
b. High safety factor allows action potential to continue more likely in event of injury
10. Effects of demyelinating diseases, therapeutic effects of K+ channel blockers
a. Multiple sclerosis:
i. Sever impairment of nervous function
ii. Loss of myelin
1. Increases Cm (myelin affects membrane not axon thickness)
2. Reduces Rm
3. Na channels in nodes become dispersed
b. 4-aminopyridine:
i. K channel blocker
ii. Improves ability to control movement
11. Electrical propagation of action potentials from cell to cell
a. Uses gap junctions to propagate action potential (electrical mechanism)
b. Spans two membrane bilayers of 2 difference cells
c. Ex: heart muscle
12. Electrical vs Chemical Mechanisms
a. Electrical:
i. Use special junctions called electrical synapses
ii. Allows cells to work and contract synchronously like in the heart
b. Chemical:
i. Occurs in synapses
ii. Uses chemical transmitters

Neural Control of Organs I:

1. Subdivisions of the CNS vs. PNS, sensory vs motor, somatic vs visceral
a. CNS:
i. Parts:
1. Brain
2. Brainstem
3. Terminal cranial (CN 0)
4. Olfactory cranial
5. Optical cranial
6. Retina
7. Spinal Cord
ii. Oligodendrocytes myelin
iii. Axons cannot regenerate
b. PNS:
i. Parts:
1. Ganglia, nerves from CN III-XII
2. Spinal Nerves
ii. Schwann Cells myelin
iii. Axons can regenerate (if spinal cord cut cannot regenerate)
c. Sensory vs Motor:
i. In both CNS and PNS
ii. Sensory:
1. Afferents
2. In dorsal root ganglion of PNS
iii. Motor:
1. Acts on organs, cause action
2. No immediate feedback
3. Anterior horn of spinal cord
4. Motor axons come from CNS
5. Body of motor cells in spinal cord
d. Somatic vs. Visceral
i. Somatic = motor, moves in conscious way
ii. Visceral = unconscious actions
1. ex: innervation of heart, swallowing

2. Differences among somatic and autonomic visceral motor systems

3. Subdivisions of autonomic visceral motor system

a. Parasympathetic:
i. AcH
ii. Originates from midbrain + sacral
iii. Preganglionic = long
iv. Postganglionic = short
v. Uses all muscarinic Ach receptors
b. Sympathetic:
i. Epinephrine
ii. Originates from thoracic + lumbar
iii. Preganglionic = short (muscarinic Ach receptors)
iv. Postganglionic = long (norepinephrine receptors, except Sweat glands: Ach)
1. Adrenal medulla secretes epinephrine/norepinephrine into blood

4. Role of reflex arc: (connection between neurons)

a. Occurs in response to stimulus without conscious influence
b. Most nervous system acts by reflexes
c. Unconscious allows automatic regulation
d. Somatic Reflex: muscle/tendon
i. Ex: knee jerk (1 synapse)
e. Visceral Reflex: at level of organs:
f. Short (mono) and Long (di/polysynaptic) Reflex
g. Intrinsic (born with) and Acquired Reflex
5. Role of autonomic control centers in brain:

a. Medulla + Hypothalamus integrate 3 systems:

i. Autonomic
ii. Endocrine
iii. Part of CNS that deals with motivation and emotion
6. Sensory inputs of autonomic control centers in brain:

Leptin and insulin goes through

BBB using specific transport
mechanism b/c insulin is big
peptide

7. Circumventricular organs of brain:

a. Median Eminence:
i. 3rd ventricle
ii. Does not have BBB
iii. Contains arcuate nucleus
iv. Measures hormone levels in blood
v. Controls basal level hormones
vi. Directs release of hypophyseal hormones
vii. Part of inferior hippocampus
b. Organ Vasculosum of Lamina Terminalis:
i. Determines osmolarity of serum
ii. Can make you thirsty
iii. Supraoptic nucleus: fluid electrolyte balance
iv. Preoptic Nucleus: regulates LHRH
v. Suprachiasmatic nucleus:
1. tells pineal gland to release melatonin
2. releases GH
c. Subfornical Organ:
i. In front of foramen of Monroe
ii. Contains hippocampal mammillary tract
iii. Contains angiotensin II receptors
1. Responds to decreased concentration of serum
iv. Projects to supraoptic organ + lamina terminalis
v. Releases ADH
d. Pineal Gland:
i. Highly vascular
ii. Releases melatonin into CSF of 3rd ventricle
1. mediated by epiphyseal cells
e. Under Posterior Commissure Subcommissural Organ
i. BBB free area
ii. Capillaries are not fenestrated
iii. Epithelial gland cells
iv. Located at beginning of aqueduct of Sylvius
v. Controls 3rd and 4th ventricle CSF movement or compounds
f. Area Postrema:
i. Floor of 4th ventricle
ii. Modified astrocyte
iii. Vomiting center of brain
iv. Ionotropic receptors
v. Removes toxins in body
vi. Most critical chemosensor in brain
vii. Gut peptides from gut in bloodstream sensed by postrema
g. Posterior Pituitary
h. Sensory: area postrema, OVLT, subfornical organ
i. Secretory: posterior pituitary, median eminence, pineal gland, subcomissural organ

j.

Features:
i. Fenestrated between endothelial cells lining vasculature
1. no tight junctions
2. regular CNS cells have tight junctions
ii. High blood volume to tissue weight ratio
iii. High density of receptors for blood circulating signals of autonomic state

Important Table:

Neural Control of Organs II:

1. Synaptic and non-synaptic modes of neurotransmission
a. Synaptic:
i. Fastest
ii. In CNS
iii. Few junctional
b. Non-synaptic:
i. Majority of transmission in nervous system
ii. Junctional = paracrine
1. Close (fast)
2. Wide (slow)
iii. Remote = endocrine
1. CSF (fast)
2. Via Blood (slow)
iv. Ex: autonomic neural control of smooth muscle, immune, epithelial, and
endothelial cells
2. Types of intercellular signaling: juxtacrine, autocrine, paracrine, and endocrine
a. Juxtacrine: transmitted via protein or lipid components of membrane and is capable of
affecting either the emitting cell or cells immediately adjacent
b. Autocrine, Paracrine, Endocrine: already discussed previously
3. Neuronal and non-neuronal synapses:
a. Neuronal synapse: at point where two communicating cells meet
i. Intercalated discs in heart is similar to synapses in neurons
b. Non-neuronal: point where T cell comes to attack invading cell
4. Mechanisms of synaptic transmission: electrical and chemical
a. Electrical:
i. Direct flow of current through gap junction
ii. Passes through specialized proteins connexons
1. 2 parts
2. Each part made of 6 connexins
3. Connection of two connexons form gap junction
4. Feature of multicellular
organisms
iii. Uncommon, mostly in CNS
iv. Rapid signal conduction
b. Chemical:
i. Majority of synapses
ii. Uses neurotransmitters to relay info

5. Nerve terminals: varicosities, buttons, end plates, En passant varicosities

a. End plates:
i. Specific arrangement of buttons
b. En Passant Varicosities:
i. Characteristic for visceral innervation
ii. In smooth muscle cells of gut
iii. Principle for neural innervation, not synapses
iv. Neural transmitter released from varicosities
v. Paracrine
vi. Smooth muscles electrically coupled by gap junctions (2 connexons)
6. Neuroeffector junctions: somatic, visceral, vascular
a. Somatic:
i. neuromuscular junction
ii. use Ach (barely found in plasma)
b. Visceral/Vascular:
i. Doesnt have to be synaptic
ii. Terminal portion of autonomic nerve fibers are varicose
iii. Transmitters released from varicosities at various distance from effector cell
iv. No structural post junctional specialization on effector cells
v. Receptors for neurotransmitters accumulate on cell membrane at close
junctions
c. Difference between visceral/vascular:
i. Vascular: close to blood vessels
ii. Visceral: specific to smooth muscles + organs
7. Somatic neuroeffector junction (neuromuscular junction) is a chemical synapse
a. Skeletal muscle fiber innervated by single -motorneuron
b. All fibers innervated by same axon = motor unit
c. Neuromuscular junction formed by axon = end plate
d. Presynaptic button:
i. covered by Schwann cells
ii. in synaptic cleft (depression on muscle fiber)
iii. contains Ach
iv. Ca2+ influx causes vesicles to fuse with presynaptic membrane
1. Low extracellular Ca2+ = reduced Ach released
e. Sarcolemma of end plate has nicotinic Ach receptors
8. Synthesis and recycling of acetylcholine (AcH): ChAT and AChE
a. Ach is pentamer (5 subunits)
b. Inside presynaptic button:
i. Cholineacetyltransferase (ChAT) reacts with choline Ach
ii. Ach released
c. Ach binds to postsynaptic receptor
d. AChE (acetylcholinesterase) unbinds Ach from receptor

9. Nicotinic Ach receptor is a ligand-gated channel

10. Quantal nature of synaptic transmission. Mechanism of ACH release
a. Ach is packaged in discrete vesicles
b. Integer number of vesicles is released
c. Apparent in low Ca2+ concentration less Ach is released able to count
d. Mechanism:
i. Specific transport proteins in vesicle membrane use energy of H+ gradient to
energize uptake of Ach into vesicles in presynaptic button
ii. Action potential arrives involving Na-K channels
iii. Depolarization opens Ca2+ channles Ca2+ enters
iv. Ca2+ triggers fusion of vesicles with presynaptic membrane Ach released
v. Termination:
1. Enzyme
2. Reuptake
3. Diffusion away from synapse
11. Drugs affecting neuromuscular junction. Diseases of nicotinic AChR
a. Tetrodotoxin
i. Blocks Na channels
ii. No depolarization
b. Molluscan:
i. Blocks Ca2+ channels
ii. Prevents release of Ach
c. Botulinum
i. Binds to presynaptic membrane
ii. Prevents release of Ach
d. Curare
i. Binds to AChR (receptor of ach)
ii. Prevents binding of ach
e. Myasthenia gravis
i. Autoimmune disease
ii. Block of AChR by anti-AChR antibodies
iii. Muscle weakness
f. Lambert-Eaton Syndrome:
i. Autoimmune
ii. Attack on presynaptic Ca2+ channels
12. A two-transmitter view of autonomic nervous system
a. Sympathetic:
i. Preganglionic: Ach ionotropic nicotinic receptors
ii. Postganglionic: NE metabotropic and -adrenergic receptors
b. Parasympathetic:
i. Preganglionic: Ach ionotropic nicotinic receptors
ii. Postganglionic: Ach metabotropic muscarinic (G-protein) receptors

13. Adrenaline. Nor- or not, whats the difference? NANC transmitters

a. Epinephrine = adrenaline
i. Increases 50x in stress
ii. Mostly from adrenal medulla
iii. Hormone, not neurotransmitter
b. Norepinephrine:
i. Mainly produced by nerve terminals in vasculature by varicosities
ii. Little produced by adrenal medulla

Question marks replaced

by: up, down, up, up
Stimulatory receptors: 1
and 2

c. NANC (non-adrenergic, non-cholinergic) autonomic transmitters: many in gut

i. Neuropeptide Y
ii. Nitric Oxide
iii. Vasoactive Intestinal Peptide
iv. ATP

14. Co-transmission at nerve terminals of both pre and postganglionic neurons of

autonomic motor system
a. Ganglionic Synapse (Ach)
i. Ach can activate both nicotinic and muscarinic receptors
ii. Produce fast and slow postsynaptic response
b. Neurovascular Junction (Norepinephrine)
i. 1-adrenergic receptor on postsynaptic area vasoconstriction
ii. 2-adrenergic receptor on presynaptic membrane to inhibit further release
c. Secretomotor Junction (Ach + VIP)
i. Co-transmission
ii. Parasympathetic postganglionic nerve terminals in salivary gland release Ach
and vasoactive intestinal peptide (VIP) to control secretion

Muscles: Conversion of Chemical Energy (ATP) into Mechanical Force

1. Types of muscle tissue: skeletal, cardiac, and smooth.
a. Skeletal:
i. Multiple nuclei
ii. Striated
iii. Responsible for voluntary movement
iv. Innervated by somatic motor system
v. Enclosed by tough connective tissue to form muscle
vi. One transmitter, one synapse
b. Cardiac:
i. Multiple nuclei
ii. Striated
iii. Cells branched
iv. Cell connected by intercalated discs (electrical current can flow)
v. Only in heart wall
vi. Allows involuntary heart beat
c. Smooth:
i. Single nucleus
ii. NOT striated
iii. Cells held together by tight junction and tapers at ends
iv. Located in hollow organs (blood vessels, GI tract, bladder)
v. Involuntary movements (peristalsis)

2. Membrane architecture of striated muscles

a. Sarcomere: basic unit of skeletal muscle (1-2 microns)
b. Sarcomere < Myofilaments < Myofibrils < Muscle fiber < Muscle fasciculus
c. Each fiber surrounded by electrically polarized membrane sarcolemma
d. T-tubules invaginate from sarcolemma and form junctions with Sarcoplasmic
Reticulum
e. T-tubule every 2 microns
f. SR stores Ca2+
g. SR network surrounds myofibrils
h. Striated triads (2 SR + T-tubule)

3. Difference between Cardiac and Skeletal

a. Cardiac:
i. Smaller cells
ii. T-tubules:
1. Shorter and broad
2. Diad
3. Encircle sarcomere at Z lines instead of overlap
iii. SR
1. lacks terminal cisternae
2. tubules contact both cell membrane and T-tubules
iv. intercalated discs (gap junctions + desmosomes)
v. Functional syncytium
1. Chemically, mechanically, electrically connected
2. Resembles enormous muscle cell
4. Structural differences between striated and smooth muscles
a. Smooth:
i. No t-tubules
ii. No myofibrils
iii. No sarcomeres
iv. Contracting cell twists like corkscrew (fishnet contraction)
v. Has dense bodies:
1. Where filaments attach
2. Part of intermediate filament network (cytoskeleton)
3. Binds adjacent muscle cells
4. Allows transmission of contractile forces from cell to cell
vi. Many not innervated by motor neurons
vii. Multiunit:
1. resemble skeletal and cardiac
2. neural activity produces AP
3. Location: iris, male reproductive tract, walls of large arteries
4. Not in digestive tract
viii. Visceral:
1. Arranged in sheets or layers

2. Connected by gap junctions

3. Have rhythmic cycles in absence of neural stimulation (digestive)
4. Spontaneous depolarization
5. Importance of intracellular Ca2+ signaling for muscle contraction
a. Ca2+ is secondary messenger
b. Increase in Ca2+ usually indicates muscle contraction
c. Ca2+ is released from terminal cisterns of SR once AP reaches it
i. AP reaches DHPR (voltage sensor) on T-tubule
ii. Communicates with RyR, which releases calcium at SR
d. Ca2+ diffuses to actin and myosin filaments
e. Ca2+ binds to troponin C, which is on tropomyosin
f. Binding allows tropomyosin to move away from actin myosin can now bind
g. Rowing motion begins
h. High Ca2+ concentration outside SR causes calcium-ATPase to be activated
i. Pump brings Ca2+ back to SR tropomyosin restored to blocking binding sites
6. Excitation-Contraction Coupling (ECC) in the 3 kinds of muscles. Link between
excitation and intracellular Ca2+ release. Major differences in mechanisms of
intracellular Ca2+ release.
a. Excitation-Contraction Coupling: process of converting excitation through AP or
electrical event to a force (mechanical event) due to myosin/actin.
b. Skeletal ECC:
i. Steps:
1. Conformational change of DHPR (voltage sensor)
2. Structural rearrangement of DHPR
3. RyR1-DHPR interaction.
4. RyR1 channel opens
ii. AP ends by time calcium channels open (peak Ca2+ at 5ms)
iii. Peak tension = 25ms
iv. Gating potential determines AP, not Ca2+ that moves through it
v. Depends on direct coupling of DHPR/RyR1
vi. Action Potential permeability of sarcolemma to extracellular Ca2+ ions

c. Cardiac ECC:
i. Steps:
1. Conformational Change of DHPR
2. Structural rearrangement of DHPR
3. L-type Ca2+ channels open Ca2+ enters cell
4. Ca2+ binds to RyR2 causing structural rearrangement
5. RyR2 channels open
ii. Calcium induced/Calcium released NOT by voltage
iii. Calcium influx vital to EcC
iv. AP lasts much longer and plateaus
v. Calcium channels open and close during AP plateau
vi. Peak tension = 150 ms
vii. Positive feedback calcium moving inwards induces more calcium
viii. Contraction
1. Determined by pacemaker cells
2. Neural stimulation not needed
3. Done through automaticity
4. Cannot undergo summation or tetanic contraction

d. Smooth ECC:
i. Action Potential NOT needed stimulated by (either/or)
1. Depolarization (electromechanical)
2. Hormones (chemo-mechanical)
ii. Triggered by Ca2+ ions from extracellular fluids
iii. No linkage between length and force
iv. Myogenic tone:
1. If pulled will contract
2. Regulated by mechanical regulator in cell instead of external
actions
v. No troponin
vi. Myosin is activated by phosphorylation following rise in Ca2+
1. Actin is not acted upon like in skeletal muscles
2. Myosin Light Chain Kinase (MLCK) is activated when it binds to
calmodulin that is bound to Ca2+
3. MLCK phosphorylates myosin can power stroke
4. Dephosphorylation done by phosphatase (MLCP)
a. Inhibited by hormones
vii. Force is sustained after stimulation by hormone, but not by depolarization
viii. Ca2+ sensitization and L-type Ca2+ channels maintain contraction
ix. If hormone used, less Ca2+ needed due to reduced control of MLCP
7. Contractile machinery in 3 kinds of muscle. Proteins involved. Actin-myosin interaction
cycles. Role of latch state in smooth muscle. Electromechanical and chemo-mechanical
ECC in smooth muscle.
a. Latch State (smooth muscle)
i. Rather than having tetanic contraction, smooth muscles use a latch system
to allow prolonged contraction without constant use of ATP

b. Everything else is mentioned in questions #6

Extra Info:

Peripheral Proteins: remove through acid or salt

Integral Proteins: remove through detergent
Solution: molecular mixture, homogeneous
Body Fluid Compartment:
o 60% body weight = water
o 40% = ICF
o 20% = ECF
RBC in Solution:
o Hypotonic lyse
o Hypertonic shrivel
Smooth Muscle is often near entrance to capillaries
o Regulates amount of blood flow into each vessel
o If tissue oxygen starved smooth muscle relaxes blood flow increases more
oxygen
Hyperkalemia: high K+ serum levels
o Causes resting potential to be raised
o Muscles are depolarized, but inactivation gates of Na+ are closed thus no action
potential can occur
o Ultimately, muscle weakness
Reflection Coefficient:
o If 1 solute is impermeable water flows (ex: albumin, large particle)
o If 0 solute is completely permeable no water flow (ex: urea)
Poisoning Na-K Pump:
o Inhibits Na-Ca exchange:
Because more Na+ remains intracellularly, Na+ from outside will not go
down its gradient and thus no Ca2+ will move out
o Inhibit Na-glucose cotransport:
Na+ will remain intracellularly, thus co transport cannot happen since no Na+
gradient
o Decreases Na+ out of cell decreases resting membrane potential once passive
transport of Na and K takes place inhibits secondary active transport
Inhibitors of Na-K Pump:
o Causes increase in cell volume due to osmotic entry of water
o Ouabain
o Digitalis
o Low pH
Activators of Na-K Pump:
o Insulin
o Aldosterone
Tetanus:
o Increases Ca2+ levels intracellularly
o Causes extension of cross-bridge cycling
o Muscles cannot relax Tetanus
Force-Length Relationship of Muscles:

o
o
o
o

Consequence of sliding filament mechanism

Max isometric contraction = 2 2.5 micrometers in sarcomere length for skeletal
Stretching cardiac muscles increase force of contraction (Frank Starling Law)
Active tension: force developed from contraction of muscle
Proportional to number of cross-bridges formed
Max overlap of thin/thick = max tension
Stretched muscle = less overlap
o Passive tension: tension by stretching muscle
Extracellular Signals:
o Endocrine: insulin, epinephrine
o Local: cytokines, histamines, prostaglandins
o Neurotransmitters: Ach, glutamate
Effects of Signal Transduction:
o Long Term: alteration in gene expression alters protein synthesis (ex: steroids)
Nuclear receptors interact with DNA elements + regulatory proteins
o Short Term: altering protein function (phosphorylation)
Formation and Degradation of cAMP:
o Adenylyl Cyclase: formation
o cAMP phosphodiesterase: degradation
Protein Kinases:
o Tetramer
o PKA holds 4 cAMP
o Inactive forms are regulators (2 inactive, 2 active)
o Phosphorylates on serine, threonine, or tyrosine residues
Calmodulin
o Binds 4 Ca2+ ions
o Inactive when folded up
Motor Neuron vs. Skeletal Muscle Fiber Action Potential:
o Muscle Fiber more negative (-90)
o On down end of AP:
Motor Neuron: hyperpolarization
Skeletal Muscle: depolarization (getting more negative, but always remains
more positive in relation to resting potential)
Sodium Channel Blockers and Anesthetics promote refractory period
o Acts on inactivation gates
o During refractory periods Na+ inactivation gates closed
Multiple Sclerosis:
o Loss of mylin
o Treatment
K Channel Blockers (4-aminopyridine)
Cystic Fibrosis:
o Mutation of CFTR (calcium channel) deletion of phenylalanine
o Secretion of Cl- and water is reduced mucous secretion
o Na+ channels on apical side are increased increased water and Na+ reabsorption
o Treatment:
Blocking Na+ influx with amiloride or activating other Cl- channels