Section I: Introduction
Chapter 1
FOUNDATIONS OF PHYSIOLOGY
The dynamic study of life. Inevitably intertwined with
copious descriptions of structure, as form and function
correlate at levels of life.
Various levels of reductionism seen in different studies in
and interpretations of physiology, e.g. whole person, an
organ system, etc.
Homeostatic Mechanisms
An endless number of vital parameters in the body are kept
in a narrow range, from the cellular level to the organism
level. One of the most common themes in physiology is the
negative feedback mechanism. Requires at least four elements:
1. The system must be able to sense the vital parameter or
a something related to it (a function of it)
2. A reference value to compare with, called the set point,
to form a difference (error) signal
is, the more vital a parameter is, the more feedback loops
3. The error signal must be multiplied by some
proportionality factor (i.e., the gain) to produce some
sort of output signal
4. Finally, the output signal must produce an activator
signal that opposes the source of the error signal and
therefore bring the vital parameter closer to the set
point.
Feedback loops don’t operate in isolation, but rather as
part of complex networks, working in either synergism or
antagonism with other loops. Feedback loops acting on the
same or related parameters may have different weights in
competition with each other. Hierarchy is another type of
relationship between different loops. For example, the
hypothalamus controls the anterior pituitary, which in turn
controls the adrenal cortex, which releases cortisol, which
helps regulate blood glucose levels.
Redundancy is another recurring theme in homeostasis; that
affecting it. The result numerous feedback systems regulating
vital parameters is a pretty constant milieu interieur.
Homeostasis occurs at a price: energy. When a parameter is
held at a constant value, then it is necessarily not in
equilibrium, but rather in a steady state. That is, it is constant
because the body carefully matches actions that lower its
value with other actions that increase it, and vice versa.
Each cell plays a specialized role in the overall function of
the body. In return, the body provides the cell with a constant
internal milieu to live in; a bargain. As part of this bargain,
each cell must put the needs of the body in priority. For
example, during exercise, the body sheds excess heat by
elaborating sweat for evaporation. However, the production
of sweat reduces blood volume. Since the body puts a higher
priority on blood volume rather than on body core
temperature, sweat production is ultimately stopped to cease
blood volume decrease. This compromise works only if the
person stops exercise, if not, heat shock may occur.
The adaptability of an organism depends on its ability to
modify its response, in turn in response to changing
conditions. Flexible feedback loops lie at the root of many
physiological adaptations. For example, experimentally
lowering the level of oxygen in inspired air causes an increase
in breathing rate. However, after acclimatization to higher
altitudes, this response is amplified. Adaptation can also
occur at the population genetics level; for example,
populations of humans who have lived at high altitudes can
withstand hypoxia better than lowlanders, even acclimatized
individuals.
Medicine, the Study of “Physiology Gone Awry”
Medicine uses physiology as a “reference state”.
A large part of medical physiology is dealing with the
abnormal physiology brought about by a disease process.
One malfunction (e.g., heart failure), can lead to a primary
pathological effect, (e.g., a decrease in heart output) that –in
chain reaction style- leads to a series of secondary effects (e.g.,
fluid overload) that are the appropriate responses of
physiological loops (not to be confused with necessarily
feedback loops).
Physiology of Cells & Molecules

Functional Organization of the Cell
Active transport and selective permeability lie at the heart
of many physiological processes.
When gradually added to an aquatic solution,
phospholipids begin to assemble into micelles at a specific
concentration. At still higher concentrations, they from lipid
bilayers.
Detergents can dissolve phospholipids because of their
amphipathic nature. They possess a very hydrophilic head
group and a hydrophobic tail.
The rate of 2D diffusion across a membrane leaflet is quite
temperature-dependent and demonstrates the somewhat
binary transition of the membrane from sol (“liquid”) to gel
state. This temperature at which this transition occurs is called
the transition temperature.
Sphingolipids: derivatives of sphingosine. Consist of three
groups: sphingomyelins, glycosphingolipids, and
gangliosids.
Chapter 2
At modest concentrations, cholesterol can decrease
membrane fluidity, but at higher concentrations it severely
disrupts the association of membrane phospholipids, thus
increasing fluidity.
Bilayers consisting of several types of phospholipids don’t
undergo the sol-gel transition at clear-cut temperature. Their
transition is of a more gradual nature, enabling the existence
of distinct “gel-like” and “sol-like” domain across the
membrane.
Cholesterol, unlike phospholipids, can easily undergo flip-
flop motions.
The membrane leaflet facing the cytoplasm consists of PS
and PEA, but the extracellular leaflet consists almost entirely
of PCh.
Two types of membrane proteins: peripherally associated
and integral.
 Peripheral protein do NOT enter the hydrophobic
environment of the membrane, unlike integral proteins. They
can be removed from the membrane by mild treatments such
as very low salt concentrations (which disrupt hydrogen
bonds) and very high salt concentrations (which disrupt ionic
bonds).
Adding detergent to protein-containing membranes
separates the proteins as detergent micelles.
Membrane proteins have a very low innate diffusion rate
because of their large size. Their diffusion can be regulated
such as fixing by means of the cytoskeleton or accelerated
locomotion by motor proteins.
Functional classification of membrane proteins: receptors,
adhesion molecules, pumps, carriers, channels, enzymes (e.g.
located on the luminal side of the intestinal cells’ membrane,
include many GPI-anchored extracellular proteins), proteins
forming a sub-membrane cytoskeleton through their
associations.
The cell’s digestive organelle, the lysosome, contains several
internal vesicles called exosomes within its internal space.
The NPC halts the diffusion of intrinsic membrane proteins
between the inner and outer membranes of the nuclear
envelope. So their protein reservoirs are not the same.
The mitochondrial storage of Ca2+ is released during energy
starvation, which causes cell injury and death.
Microtubules provide the framework for the lacy
membranes of the ER and Golgi apparatus. Their disruption
causes dramatic morphological changes in these organelles.
Kinesis moves in minus-to-plus direction, whereas
cytoplasmic dynein moves in plus-to-minus direction along
microtubules.
Because the ER membrane has a finite number of docking
sites, which is insufficient to match the rate of protein
synthesis, the cell must coordinate the synthesis of membrane
and secretory protein with the availability sites. Were there
no such coordination, the synthesis of
membrane and secretory protein would
continue without docking, entirely within
the cytosol. The SRP cycle serves as a
regulatory system that matches the rate of
protein synthesis with the number of
available docking sites. By associating with a
nascent signal sequence, the SRP halts
further peptide elongation.
When the SRP complex contacts a docking
protein, the SRP hydrolyzes its bound GTP,
thus releasing the signal sequence. Delivery
of a nascent chain to a translocon causes the
entrance of the translocon’s channel, which is normally
closed, to open. This opening also allows the flow of small
ions.
For integral membrane proteins, the hydrophobic amino If the more positively charged flanking residues of the stop-
acid residues that will ultimately become the protein’s transfer sequence are at the amino terminal, then the protein
transmembrane segment also act as a stop-transfer sequence will be oriented with its amino terminal in the cytosol, and vice
during its translocation, maintain its correct topology relative versa. Remember the negative outside rule (outside refers to the
to the membrane. mitochondrion).
 Somatic cells express special membrane proteins to protect
themselves against the complement system’s false-positive
attacks.

GPI-linked proteins are synthesized as transmembrane

polypeptides, with a typical membrane spanning region.
Shortly after their translation, however, their lumen facing
domain are cleaved from the membrane spanning segments
and covalently transferred to the GPI phospholipid.
Chaperons allow protein folding to progress in orderly
fashion through energy provided by ATP hydrolysis.
 It is not clear if the assembly of the subunits of oligomeric
proteins is spontaneous or mediated by special systems.
In the ER, proteins that have not folded or assembled
correctly are destroyed through a process called ERAD.
They’re first retrogradely translocated, then poly-
ubiquitilated, which results in their degradation in the
proteasome.
Generally, there are two types of secretory pathways,
constitutive and regulated. In the regulated pathway,
secretory proteins are not secreted continuously, but they
rather reside in specialized secretory vesicles and are secreted in
response to a specific signal. The regulated and constitutive
pathway are essentially identical except for the final station at
the Golgi complex.
The rate of new membrane lipid and protein synthesis in the
ER is less than the rate at which carrier vesicles bud off of the
ER that is bound for the Golgi. This is balanced by backflow
of the vesicles in the constitutive pathway.
The cell has at least to types of coat proteins for vesicles.
Clathrin mediates vesicular transport from the TGN to the
plasmalema and endocytosis, while coatamer mediates
vesicle transport between the ER and the Golgi and between
different Golgi stacks.
The formation of the clathrin is spontaneous, so it is its
dissolution that requires energy.
Unlike clathrin, the formation of coatamer cages is not
spontaneous, and a coatamer-coated vesicle retains its coat
until it reaches its destination.
The SNARE protein is the protein that senses
Ca2+concentration rise during NT release. Membrane fusion
requires the participation of a special class of monomeric
GTPases called Rabs that are important for signaling. Rabs
appear to act as molecular switches that that assemble with
the SNARE fusion complex when they are binding GTP but
dissociate from the complex when they hydrolyze it to GDP.
Numerous Rab isoforms exist, each associated with a
different vesicular component and a distinct membrane-to-
membrane translocation step.
Once fusion occurs, the former vesicle loses its spherical
shape as it becomes incorporated into the target membrane.
This “flattening out” is mainly the result of surface tension
and also the fact that the tight angles in its spherical shape are
energetically unfavorable for its phospholipids.
The dissociation step the participation of two additional
proteins in the complex. The first is an ATP-hydrolyzing
enzyme; since it is inhibited by the alkylating agent NEM (N-
ethylmaleimide), it was named NEM-sensitive fusion factor
(NSF). Soluble NSF attachment proteins (SNAPs), which
target the NSF to SNARE complex, are the second.
The final residue of the terminal sugars of glycoproteins is
frequently N-acetylneuraminic acid, a.k.a sialic acid. This
acidic sugar residue is responsible for the net negative
electrostatic charge carried by glycoproteins.
Proteins bound for different destinations cluster in different
subdomains of the TGN.
A special class of mannose 6-phosphate receptors reside in
the TGN and function to carry proteins containing M6P
groups to lysosomes. After budding off from the TGN
membrane, these vesicles lose their clathrin coats and fuse
with structures referred to as late endosomes or prelysosomal
endosomes. When exposed to the acidic environment of the
lumen of these vesicles, these M6P receptors dissociate from
their ligands and retrogradely transported back to the TGN
membrane.
 When endocytising material, the cell must segregate that hydrolyze complex sugars and peptides are restricted to
material that is to be degraded in the lysosome from material apical cells in the intestinal cells.
that is to be recycled back to the plasmalema. The sophisticate Different mechanisms participate in the sorting of proteins
operation for this segregation takes place in the endosome. bound for different destinations in the secretory pathway.
When in the low pH environment of the endosome, receptor One of them is the aggregation of GPI-linked proteins into
proteins release their ligands and aggregate at a special “glycolipid rafts” in the Golgi apparatus membrane, finally
subdomain of the endosome’s membrane, and ultimately bud budding into vesicles bound for the plasma membrane.
off as a vesicle bound for the plasmalema. The rest of the
material in the endosome is to be delivered to a lysosome.
A variation on this paradigm is seen in the iron transport
system. Iron circulates in the plasma bound to a protein called
transferrin. At the mildly alkaline pH of the ECF, the iron-
transferrin complex binds with high affinity to a transferrin
receptor in the plasmalema. The acidic environment of the
endosome causes the separation of iron from the transferrin.
Apotransferrin binds the transferrin receptor tightly at acidic
pH, and is subsequently recycled back to the plasma
membrane, where the alkaline pH of the ECF causes
Apotransferrin to release its receptor.
The Na-K pump is restricted to the basolateral membrane in
almost all epithelial cells, and the membrane-bound enzymes