1

Lecture 1: Principles of Systemic Physiology

Reading: chapter 1

Levels of Organization
(1) Chemical Basic molecules of life are proteins, carbohydrates, fats and nucleic acids
(2) Cell
Functions:
obtain nutrients and oxygen
metabolism
synthesis
exchange of materials
intracellular transport
reproduction
(3) Tissue Aggregate of cells and extracellular material. 4 main types:
Muscle (contraction)
skeletal
cardiac
smooth
Nervous (transmission of signals)
central
peripheral
Epithelial (exchange of materials)
epithelial sheets (form boundaries)
glands (secretion of synthesized materials)
Exocrine (external secretion)
Endocrine (internal secretion)
Connective (structural support)
tendons
bones
blood
(4) Organ Two or more primary tissues organized to perform a function
e.g. Stomach: composed of all 4 tissue types
Epithelial
epithelial sheet - barrier to digestive juices
exocrine gland - secretes digestive juices
endocrine gland - regulates exocrine secretion
Muscle
smooth muscle - stomach wall
Nervous
peripheral nerves - regulate contraction
Connective
structural support
(5) Organ System Collection of organs that perform related functions essential to survival
Circulatory System
heart, blood vessels, blood
Digestive System
mouth, pharynx, esophagus, stomach, small intestine, large intestine, salivary glands,
pancreas, liver, gall bladder
Respiratory System
nose, pharynx, larynx, trachea, bronchi, lungs
Urinary System
kidneys, ureters, urinary bladder, urethra
Skeletal System
bones, cartilage, joints

2
Muscular System
skeletal muscles
Integumentary System
skin, hair, nails
Immune System
white blood cells, thymus, bone marrow, tonsils, adenoids, lymph nodes, spleen, appendix,
gut and skin-associated lymph tissue
Nervous System
brain, spinal cord, peripheral nerves, sense organs
Endocrine System
hormone secreting tissues: hypothalamus, pituitary, thyroid, adrenals, endocrine pancreas,
parathyroids, gonads, kidneys, intestine, heart, thymus, pineal, skin
Reproductive System
male: testes, penis, prostate gland, seminal vesicles, bulbourethreal glands
female: ovaries, oviducts, uterus, vagina, breasts
6) Organism
**Homeostasis = Dynamic maintenance of a stable internal (extracellular) environment within
the organism
- essential to survival of each cell
- requires continual exchange of materials between the intracellular and extracellular spaces
- each organ system contributes by counteracting changes of internal environment
Factors that must be maintained:
concentration of nutrients
circulatory, digestive, muscular, nervous, endocrine
concentration of O2 and CO2
circulatory, respiratory, muscular, nervous
concentration of waste products
circulatory, digestive, urinary, muscular, nervous, endocrine
pH
respiratory, urinary, nervous
concentration of water and electrolytes
circulatory, digestive, urinary, skeletal, muscular, integumentary, nervous, endocrine
temperature
muscular, integumentary, nervous
volume and pressure
muscular, nervous, endocrine
defense against foreign invaders
immune
Homeostasis is maintained by control systems:
Intrinsic Local control systems built into an organ
e.g. increased CO2 production leads to relaxation of smooth muscle and dilation of blood
vessels
Extrinsic External control system outside of an organ permitting coordinated regulation of several
organs
I - Nervous system
e.g. low blood pressure detected by nervous system which causes increase in heart
rate and constriction of blood vessels
II - Endocrine system
**Physiological Principles
Negative Feedback Change in a controlled variable triggers a response that opposes the change
sensor - mechanism to detect the controlled variable
set point - the desired value of the variable
integrator - compares the sensors input with the set point
effector - adjusts the value of the controlled variable
Positive Feedback Reinforces the change in a controlled variable, occurs relatively rarely
Feedforward Control Response occurring in anticipation of a change in a control variable.

Lecture 2: Principles of Cellular Physiology

Reading:

chapter 2
chapter 3: membrane structure and composition, pgs 52-57 (8th
edition)
(pgs 52-57, 7th edition)
(pgs 52-58, 6th edition)
(pgs 56-62, 5th edition)

Levels of Organization
Plasma membrane
Nucleus
Cytoplasm
Organelles
endoplasmic reticulum
Golgi complex
lysosomes
peroxisomes
mitochondria
vaults
Cytosol
Cytoskeleton
microtubules
microfilaments
intermediate filaments

Plasma membrane
Thin membrane enclosing each cell
composed of phospholipid bilayer embedded with proteins and
carbohydrates
separates intracellular and extracellular spaces
serves as a barrier to diffusion
Membrane proteins
can selectively transport molecules and ions
can act as receptors to signal responses by the cell
can form adhesions and junctions with other cells

Nucleus
Membrane bound organelle containing the genetic material
Deoxyribonucleic acid (DNA)
genetic material; directs protein synthesis; serves as genetic blueprint during cell
replication
Ribonucleic acid (RNA)
carries out protein synthesis
messenger RNA
genetic code is copied to mRNA via transcription and the message exits
the nucleus
ribosomal RNA
participates in reading the mRNA and translating it into the appropriate
protein sequence (translation)
transfer RNA
transferstheappropriateaminoacidinthecytoplasmtotheirdesignatedsiteintheprotein
beingconstructed

4
Cytoplasm

Portion of cells interior not occupied by the nucleus. Floating within the cytoplasm
are organelles, membrane-enclosed structures that carry out specific functions.
There are 6 main types similar in all cells:

Endoplasmic reticulum (ER) continuous fluid filled network of membranous

tubules
rough ER
ER membrane covered with ribosomes that synthesize and release proteins into
the ER lumen. The protein products can be secreted or transported to sites within
the cell.
ribosome
constructed in the nucleus and programmed to carry out the synthesis of a
single type of protein
smooth ER
ER membrane lacking ribosomes that serves to package and transport
molecules synthesized in the rough ER. Portions of smooth ER bud off to form
transport vesicles that move to the Golgi complex for further processing

Golgi complex
sets of flattened, membrane-enclosed sacs stacked in layers and specialized for
processing new proteins into finished products, and directing the products to their
destinations including secretion.
exocytosis
membrane-enclosed vesicles containing finished products fuse with the
plasma membrane, thereby releasing their diffusible contents into the
extracellular fluid.

Lysosomes
membrane-enclosed sacs derived from the Golgi, contain hydrolytic enzymes to
digest and remove unwanted material. Lysosomes fuse with endocytotic vesicles
to breakdown internalized material.
endocytosis
the process by which extracellular material is brought into the cell
pinocytosis
invagination of the plasma membrane to form a pouch and internalize
extracellular fluid
receptor-mediated endocytosis
phagocytosis
invagination of the plasma membrane to form a large vesicle and internalize
large particles such as bacteria or tissue debris

Peroxisomes
membrane-enclosed sacs containing oxidative enzymes which act to remove
hydrogen from toxic molecules. This leads to the formation of hydrogen peroxide
(H2O2) which is degraded by catalase contained within the peroxisomes
catalase An antioxidant enzyme that decomposes H2O2 into H2O and O2.

Mitochondria
oval double membrane-enclosed organelles containing the enzymes responsible
for aerobic metabolism and the production of cellular energy in the form of
adenosine triphosphate.
adenosine triphosphate (ATP)

5
molecule composed of adenosine bound to three high energy phosphate
groups that serves as the energy sources for all cellular functions. Energy is
released when ATP is converted to ADP and phosphate. ATP is used for
chemical synthesis, membrane transport, and mechanical work.
Glycolysis
sequence of enzymatic reactions carried out in the cytosol in which a glucose
molecule is converted into 2 molecules of pyruvic acid and 2 molecules of ATP
are synthesized. This reaction sequence is responsible for anerobic
metabolism. The pyruvic acid molecules are transported into the
mitochondrial matrix where each is enzymatically converted to a molecule of
Acetyl-CoA and one molecule of CO2, and one molecule of NADH is
synthesized
Citric acid cycle
sequence of enzymatic reactions carried out in the mitochondrial matrix in
which the energy stored in one molecule of Acetyl-CoA leads to the formation
of one molecule of ATP, two molecules of CO2, three molecules of NADH, and
one molecule of FADH2.
NADH - (nicotinamide adenine dinucleotide-H) a derivative of B-vitamin
niacin which acts as an energy source by donating electrons.
FADH2 - (flavine adenine dinucleotide-H2) a derivative of B-vitamin
riboflavin which acts as an energy source by donating electrons.
Electron transport
sequence of enzymatic reactions requiring O2 that are carried out in the inner
mitochondrial membrane in which the donation of high energy electrons from
NADH and FADH2 lead to the production of ATP and H2O. Oxygen serves as
the final electron acceptor and combines with H+ ions to form H2O. For each
NADH molecule, 3 ATP molecules are formed and for each FADH2 molecule, 4
ATP molecules are formed
Summary
Glycolysis: Glucose => 2 Pyruvic acid + 2 ATP
Pyruvate Metabolism: 2 Pyruvic Acid => 2 Acetyl-CoA + 2 CO2 + 2 NADH
TCA cycle: 2 Acetyl-CoA => 4 CO2 + 2 ATP + 6 NADH + 2 FADH2
Electron transport: 8 NADH => 24 ATP + 4 H2O; 2 FADH2 => 8 ATP + 2 H2O
Combined:

1 glucose => 36 ATP + 6 CO2 + 6 H2O

Vaults
Octagonally shaped proteinaceous organelles which may function to transport
molecules, such as mRNA, to sites within the cytoplasm.

Cytosol
Semiliquid portion of the cytoplasm in which at least three major functions take
place:
Enzymatic regulation of intermediate metabolism
intracellular chemical reactions involving the degradation, synthesis and
transformation of small molecules such as sugars, amino acids, and fatty acids.
Ribosomal protein synthesis
proteins for use in the cytosol and elsewhere are synthesized on free ribosomes
Storage of fat and glycogen
excess nutrients are converted into fat and glycogen for storage in the cytosol

Cytoskeleton
Complex intracellular protein network that provides structural support and the
capability for transport of material and cellular movement.
Composed of 3 major components.

6
microtubules
long, hollow, unbranched proteinaceous tubes composed primarily of tubulin
and responsible for maintaining cell shape, and for controlling cellular
movements such as vesicular (axonal) transport, movement of cilia and
flagella, and distribution of chromosomes during cell division.
tubulin
small globular protein
axonal transport
bidirectional movement of large molecules and vesicles along the axon of
neurons.
cilia
motile, hair-like protrusions allowing cells to move materials across their
surface. They line the respiratory airways and the oviducts.
flagella
single, long whip-like appendage that enables cells to move thru their
environment. Form the tails of spermatozoa.
microfilaments
filaments composed of two strings of actin molecules that function in cellular
contraction and mechanical support of cellular extensions such as microvilli.
intermediate filaments
irregular thread-like protein molecules that provide structural support for
cellular components subject to mechanical stress, such as neuronal
extensions, muscle cells, and skin cells.

Lecture 3: Membrane Signaling and Transport

Reading:
edition)

chapter 3: introduction through membrane transport, pgs 52-75 (8th

(pgs 52-75, 7th edition)
(pgs 52-73, 6th edition)
(pgs 65-87, 5th edition)
chapter 4: intercellular communication and signal transduction, pgs 113117 (8th edition)
(pgs 113-117, 7th edition)
(pgs 111-113, 6th edition)
(included in the above reading if using 5th edition)

Intercellular Communication
Gap junctions
Communicating junctions that permit the passage of small molecules
Direct signaling
Extracellular protein-protein interactions
Extracellular chemical messengers
paracrine
hormone
neurotransmitter
neurohormone
How are extracellular chemicals secreted by one cell detected by
another?
1. G protein coupled receptors, coupled to 2nd messengers pathways
e.g. cAMP, IP3 pathways
These pathways ultimately bring about a cellular response by altering the
structure and function of proteins.
2. Activation of nuclear receptors The receptors for some chemical
messengers, especially lipophilic hormones, are located in the cell nucleus.

7
They are pre-bound to DNA and regulate gene transcription in response to
hormonal signaling.
3. Activation of ion channels Ion channels are membrane proteins that permit
small soluble ions such as Na, K, Ca and Cl to pass across the plasma
membrane. There are two major types: leak channels, which are always open,
and gated channels, which open and close in response to various stimuli.
Different types of gated channels are gated by changes in membrane voltage,
mechanical deformation, or binding of chemical messengers. For the latter
category, there are two types:
Ionotropic signaling Activation of ion channels by direct binding of
extracellular chemical messenger
Metabotropic signaling Activation of ion channel via 2nd messenger
pathway.

Membrane Transport
The movement of substances across the plasma membrane for the purpose of
maintaining homeostasis or carrying out specific functions. The plasma
membrane is selectively permeable to certain substances. Therefore some
substances can move passively across the plasma membrane while others must
be transported.
Selective permeability
The chemical structure of the plasma membrane (i.e. bilayer of phospholipids)
makes it selectively permeable to lipid soluble substances or to small
molecules and ions. Polar molecules or macromolecules cannot permeate the
membrane.
Passive transport
Movement of substances across the plasma membrane without expenditure of
cellular energy, via direct permeation. This type of transport can occur by
movement along an electrical or chemical gradient or by carrier mediated
mechanisms.
Active transport
Movement of substances across the plasma membrane that requires the
expenditure of cellular energy. This process may occur for substances that
must be transported against their electrochemical gradient, or for substances
for which the plasma membrane is impermeable (e.g. sugars, amino acids,
proteins). There are two general types of active transport, membrane pumps
and vesicular transport (next page).

Unassisted Membrane Transport

Two distinct driving forces act on small soluble molecules such as ions:
Concentration gradients and Electrical gradients
Diffusion down a concentration gradient
A concentration gradient exists when the bulk concentration of a molecule/ion
differs between two areas or cellular compartments. Thermal motions of the
molecule/ions cause collisions, which is turn cause a random walk from area
of higher to lower concentration. If there is nto an impenetrable barrier
between compartments and there are no additional processes at work,
diffusion ultimately results in collapse of the concentration gradient.
Movement along an electrical gradient
An electrical gradient (i.e. voltage difference) is caused by the spatial
separation of electrical charge that is created when concentration differences
among ionic molecules are established. Molecules that are electrically charged
(i.e. ions) will move in a direction along an electrical gradient that is
determined by their polarity (i.e. positive or negative charge).
Electrochemical gradient
The combined force of concentration and electrical gradients that act on

8
molecules/ions.
Rate of diffusion through a membrane depends on several factors:
magnitude of the concentration gradient
permeability of the membrane
surface area of the membrane
molecular weight of the substance
distance over which diffusion takes place
Osmosis
A special case of passive transport occurring when water diffuses down its
concentration gradient to regions of higher solute concentration. When this process
occurs across the selectively permeable plasma membrane the diffusion of water can
exert osmotic pressure.
Case 1: membrane permeable to both water and solute.
Case 2: membrane permeable to water, impermeable to solute.
Case 3: same as case 2, different initial conditions.
osmotic pressure
The magnitude of opposing hydrostatic pressure that is necessary to stop
osmosis. This pressure is proportional to the difference in solute concentrations
that exist across the plasma membrane. Because of this effect, solute
concentrations in the intracellular and extracellular spaces are kept in careful
balance to avoid substantial changes in cellular pressure or volume.

Carrier Mediated Transport

This process occurs when a substance is bound to a transmembrane protein that
undergoes a conformational change such that substance is released on the other side
of the membrane. It can be passive or active depending on the type (see below).
Facilitated diffusion
Binding of the substance directly causes the protein to change conformation and
thereby facilitate its diffusion across the membrane. It results in transport of
one or more ionic species down their electrochemical gradients. Because the
energy of binding is used to induce the conformational change, this is a passive
process. Importantly, the affinity of the binding site does not change.
Membrane pumps
A conformational change is induced by a separate energy-dependent process,
such as phosphorylation. This is an active process. It results in transport of one or
more ionic species against their electrochemical gradients. Importantly, the
affinity of the binding site does change. Examples:
Hydrogen-ion pump
Active transport protein moves H+ against its concentration gradient
*Animation*
Na+/K+ ATPase
Active transport protein that pumps Na+ out of the cell and K+ into the cell.
Three Na+ ions are pumped out for every two K+ ions in. This pump is present
in all cells and has 3 main functions:
maintenance of Na+ and K+ concentration gradients
maintenance of osmotic balance
establishment of energy gradients are used for co-transport of
other substances

Vesicular transport The movement of large polar molecules or

9
macromolecules across the plasma membrane by means of endocytosis and
exocytosis.

10

Lecture 4: Resting Potential

Reading:

chapter 3: membrane potential, pgs 75-83 (8th edition)

(pgs 75-83, 7th edition)
(pgs 73-80, 6th edition)
(pgs 87-93, 5th edition)
chapter 4: introduction through graded potentials, pgs 86-91
(pgs 86-91 if using 7th edition)
(pgs 84-89 if using 6th edition)
(pgs 98-102 if using 5th edition)

Resting Membrane Potential

This is the voltage difference that exists across the plasma membrane, expressed in
millivolts, when the cell is at rest (i.e. no perturbing influences)
Charge separation across a membrane creates membrane potential
How does the cell create charge separation?
1. Establishes and maintains concentration gradients for key ions (Na+, K+, A-)
2. Ions diffuse through the membrane down their concentration gradients
3. Diffusion through the membrane results in charge separation, creating a
membrane
potential (electrical gradient)
4. Net diffusion continues until the force exerted by the electrical gradient exactly
balances the force exerted by the concentration gradient
Concentration gradient
Macromolecular anions (A-) High intracellular concentration of nucleic
acids and proteins which carry a net negative ionic charge.
Na+ High extracellular concentration due to the Na+/K+ ATPase
K+ High intracellular concentration due to the Na+/K+ ATPase
Leak channels: Permit ions to move across membrane according to
electrochemical driving forces.
Na/K ATPase: Establishes and maintains concentration gradients
Permeability of the membrane
A- Impermeable, nearly infinite resistance
Na+ Low permeability, relatively high resistance
K+ High permeability, low resistance
Movement of K+ and Na+ ions through the membrane
Because the resistance to the flow of K+ is low, and its concentration gradient is
high, K+ tends to flow out of the cell down its concentration gradient. Because K+
ions are positively charged and the inside of the cell is negatively charged, there is
an opposing electrostatic force that attracts the K+ ions back into the cell. When
these two opposing forces, the concentration gradient and the transmembrane
voltage, become equal and opposite, there is no net flow of K+ ions across the
membrane. The transmembrane voltage at this point is referred to as the
equilibrium potential for that ion. The equilibrium potential for a particular ionic
species can be calculated using the Nernst Equation (Vm = 61 log[co]/[ci]),
where Vm is the transmembrane voltage, co and ci are the extracellular and
intracellular concentrations of the ionic species, respectively. This equation describes
the membrane voltage that exactly counterbalances the concentration gradient for a
particular ionic species:
EK = -90 mV
ENa = +60 mv

11
*If the permeability of the membrane to a particular ion transiently increases, the Vm
will shift towards the equilibrium potential for that ion.
*Animation*
Magnitude of the resting potential
Most (not all) of the resting membrane potential, is due to the flow of K+ ions. This
is because the resting permeability of the membrane is highest to K and so Vm tends
to be dominated by EK (-90 mV). Two other factors contribute to the resting
membrane potential in neurons. The first is passive flow of Na+ down its
electrochemical gradient. Although the plasma membrane has a low permeability to
Na+, there is a high electrochemical gradient acting to pull Na+ into the cell.
Therefore the passive flow of Na+ into the cell tends to make the transmembrane
potential more positive. The Na+/K+ ATPase transports 3 Na+ ions out of the cell for
every 2 K+ ions it transports into the cell. This results in a net movement of positive
charge out of the cell, making the inside of the cell more negative. Because of this
property, the Na+/K+ATPase is often referred to as an electrogenic pump and it
makes a small contribution to the resting membrane potential. The end result of all of
these processes acting together tends to give most neurons a resting membrane
potential around -70 mV.

Neurons
Soma: cell body of a neuron
Dendrite: membranous processes extending from the soma that receive
synaptic inputs from other neurons
Axon: a single specialized membranous process extending from the soma
that conducts action potentials
axon hillock - the initial portion of the axon extending from the soma.
The site at which action potentials are most commonly generated.
axon terminal - the distal end of axonal fibers where chemical synaptic
transmitter is released.

Graded Potentials
Local changes in membrane potential that decay over short distances. Can occur as
depolarizations or hyperpolarizations and most often result from chemical synaptic
transmission.
depolarization - decrease in membrane polarization to more positive values
than rest. Most often produced by excitatory synaptic transmission.
hyperpolarization - increase in membrane polarization to more negative
values than rest. Most often produced by inhibitory synaptic transmission.

12

Lectures 5-6: Action Potential I and II

Reading:

chapter 4: action potentials, pgs 91-103 (8th edition)

(pgs 89-101 if using 7th edition)
(pgs 89-101 if using 6th edition)
(pgs 103-116 if using 5th edition)

Action Potential
Brief all-or-nothing reversal in membrane potential (spike), lasting on the order of 1
millisecond, that is brought about by rapid changes in membrane permeability to
Na+ and K+ ions. Initiated in axonal or somatic membranes when the membrane
potential is depolarized beyond a threshold potential and can propagate along
axonal (and dendritic) membranes at a velocity that is determined by several factors.
Because of their ability to propagate, action potentials are the primary mechanism
used by the nervous system to transfer information over long distances (i.e. up to
1000 mm).
Voltage-gated channels
Action potentials occur when Na+ and K+ channels in the plasma membrane
open in response to depolarization. Because of their sensitivity to membrane
depolarization these channels are referred to as voltage-gated channels.
Initiation of action potential
Once the threshold potential is crossed, depolarization occurs via a positive
feedback cycle.
Events underlying the rising (Na+) and falling (K+) phases of the action
potential (Figure 4-9 in 5th edition only)
*Animation*
Summary of permeability changes and ion fluxes.
Voltage-gated Na+ channel
Opens (activates) quickly (< 0.5 ms) in response to depolarization, allowing Na+
to flow down its electrochemical gradient into the cell. This movement of positive
charge into the cell causes further depolarization, which in turn causes more Na+
channels to open, which leads to more depolarization. This is an example of
positive feedback, and this property of the Na+ channel is responsible for the
all-or-nothing character of the action potential. Voltage-gated Na channels have
both an activation gate (main gate) and an inactivation gate (ball and chain). The
channel transitions between three conformations: deactivated (closed but
capable of opening), where the activation gate is closed and the inactivation
ball is not lodged in the pore. In this state, no current flows. Opening can occur in
response to depolarization; activated (open), where the activation gate is open
and the inactivation ball is not blocking the pore. Current flows thru the channel;
inactivated (closed and incapable of opening), where the activation gate is
open but the inactivation ball has swung in to block the pore. No current flows. In
addition the channel is not capable of opening in response to depolarization,
because the ball does not respond to depolarization. Removal of inactivation
(dislodgement of the ball) is dependent on repolarization back to ~ resting
potential.
threshold This is the membrane potential which, when reached, leads
inevitably to the occurrence of a spike.
inactivation Occurs more slowly than channel opening (activation) and
contributes to the termination of a spike
absolute refractory period A brief period during a spike in which a second

13
spike cannot be generated due to inactivation.

Voltage-gated K+ channel Opens in response to depolarization with a time

course that is slower than the Na+ channel. This allows K+ ions to flow out of the
cell down their electrochemical gradient, which in turn leads to repolarization of
the membrane potential as positive charge leaves the cell. Voltage-gated K
channels have only an activation gate, and therefore exist in either open
(activated) or deactivated (closed) states. Repolarization is necessary for
their deactivation.
after hyperpolarization (AHP) A brief period at the end of a spike in which
the

membrane potential is more negative than rest.

relative refractory period A brief period following a spike during which a
higher intensity stimulus is needed to generate a second spike.

Propagation
Action potentials propagate when locally generated depolarizing current spreads to
adjacent regions of membrane causing it to depolarize. Conduction velocity is
proportional to axonal diameter and is increased by myelin.
Contiguous conduction
Propagation of action potential in unmyelinated fibers. Is relatively slow and
inefficient, especially for small diameter fibers.
Saltatory conduction
Propagation of action potential in myelinated fibers by jumping from node to node
Myelin - a multilayered sheath of plasma membrane, derived from specialized
glial
cells, that wraps around axonal fibers and acts as an insulator to the flow of
current.
The sheaths occur at regular intervals (~1mm), and are interrupted by gaps in
the insulation called Nodes of Ranvier. The nodes contain high densities of
voltage-gated Na+ and K+ channels and can generate action potentials. In
myelinated axons, action potentials propagate by jumping from node to node
through a process called saltatory conduction (Figure 4-16 in 5th edition
only). This process greatly increases the speed of propagation.
Schwann Cells - myelin-forming glial cells in the peripheral nervous system.
Oligodendrocytes - myelin-forming glial cells in the central nervous system.
Demyelinating Diseases - certain diseases, such as multiple sclerosis,
result from the degeneration myelin.

14

Lectures 7-8: Synaptic Transmission I and II

Reading:

chapter 4: synapses and neuronal integration, pgs 104-113

(pgs 104-113 if using 7th edition)
(pgs 101-111 if using 6th edition)
(pgs 117-128 if using 5th edition)

Synapses
Junction between two neurons, or between a neuron and a muscle or gland that
enables one cell to electrically and/or biochemically influence another cell.
Synaptic transmission is the primary means of rapid inter-neuronal
communication in the brain
Presynaptic cell initiates the signal
Postsynaptic (target) cell receives the signal
Postsynaptic targets can be another neuron, a muscle or a gland

Electrical Synapse
A direct electrical connection between two cells, formed by a gap junction, that
allows current to pass from one cell to another. Composed of multiple proteins
called connexons. This type of synaptic connection has no delay and is less
common than chemical synapses.

Chemical Synapse
Anatomical junction between two neurons, or between a neuron and a muscle or
gland where a chemical neurotransmitter is released by the presynaptic neuron
which diffuses across the synaptic cleft and binds to receptors on the
postsynaptic neuron to exert a physiological response. The presynaptic release of
neurotransmitter, the postsynaptic response, and the removal of transmitter from the
synaptic cleft are each governed by complex mechanisms.
Presynaptic release
Neurotransmitter is concentrated into synaptic vesicles in the presynaptic
terminal, and is released through exocytosis when the vesicles fuse with the
plasma membrane. Vesicle fusion depends on the presence Ca++ ions in the
intracellular medium. Because the intracellular concentration of Ca++ is kept
very low (on the order of 100nM), Ca++ must enter the synaptic terminal from
the extracellular space. This occurs when an action potential propagates into the
synaptic terminal and strongly depolarizes the membrane, causing voltage-gated
Ca++ channels to open and allowing Ca++ to flow down its electrochemical
gradient. The entry of Ca++ promotes the fusion of the vesicles with the plasma
membrane and the neurotransmitter is released into the synaptic cleft. The
opening of Ca++ channels in response to depolarization provides the mechanism
that tightly links the release of transmitter to the occurrence of an action
potential. At any given synapse there is usually, but not always, one type of
neurotransmitter released.
Postsynaptic response
This response most commonly consists of a rapid and graded change in
membrane potential in the postsynaptic neuron referred to as a post-synapticpotential (PSP). PSPs occur when a neurotransmitter binds to a membrane
protein called the postsynaptic receptor causing it to change its conformation
and increase its permeability to one or more ions. For each type of
neurotransmitter there is a distinct class of postsynaptic receptors. PSPs can
exhibit a wide range of properties, but most commonly fall into two major
categories:

15

Excitatory Post-Synaptic Potential (EPSP)

A depolarizing potential that tends to bring the cell towards threshold for
generation of an action potential. These PSPs usually result from an increase in
membrane permeability to a combination Na+ and K+ ions. The driving force
pulling Na+ into the cell is greater than that pulling K+ out of the cell and the net
result is depolarization. The most common excitatory neurotransmitters are
glutamate
(Glu) and acetylcholine (ACh).
Inhibitory Post-Synaptic Potential (IPSP)
A hyperpolarizing potential that tends to bring the cell away from threshold for
generation of an action potential. These PSPs usually result from an increase in
membrane permeability to either K+ or Cl- ions. When the permeability to K+ is
increased, K+ will flow out of the cell. When the permeability to Cl- is increased,
Cl- will flow into the cell. In both cases, this leads to a hyperpolarization resulting
from a net decrease in the amount of positive charge inside the cell. The most
common inhibitory neurotransmitters are gamma-amino-butyric acid (GABA)
and Glycine (Gly).
2nd messenger systems
Some neurotransmitters produce postsynaptic actions indirectly through the
activation of intracellular second messengers. These are often referred to as
neuromodulators. In these systems, the binding of neurotransmitter to the
postsynaptic receptor triggers the enzymatic synthesis of molecules that can
have widespread secondary actions. The type of 2nd messenger synthesized and
its actions depend on the type of transmitter released and the class of
postsynaptic receptor that is activated. A common 2nd messenger in neurons is
cylic-adenosine-monophsphate (cAMP). Many transmitter types can lead to
changes in the intracellular production of cAMP. Dopamine and serotonin are
examples of neuromodulators.

Transmitter removal
Several mechanisms are present in chemical synapses to remove transmitter that
has been released into the synaptic cleft. The transmitter molecules can be
degraded by enzymes present in the synaptic cleft, transported back into the
presynaptic neuron by active transport, or can diffuse out of the cleft. Each of these
mechanisms reduces the duration of action of the transmitter and ensures that its
action will be brief.

Examples of drug actions

Many drugs exert their actions on the nervous system by influencing one or more
of the processes listed above. These actions are usually either antagonistic or
facilitory.
transmitter release - tetanus toxin blocks release of GABA
transmitter uptake
- cocaine blocks the reuptake of Dopamine
- SSRIs (selective serotonin reuptake inhibitors such as Prozac, Zoloft or
Paxil) block the reuptake of serotonin
transmitter removal - many insecticides block the degradation of ACh
transmitter binding
- curare blocks the postsynaptic action of ACh at the neuromuscular junction
- THC is an agonist for the endogenous cannabinoid receptor

16
2nd messenger pathway
- caffeine enhances the action of cAMP at adrenergic synapses

Synaptic Interactions and Neuronal Integration

Neuronal networks are wired together according to two simple anatomical principles.
A given neuron can receive thousands of synaptic inputs from many other neurons
through convergence of these inputs. And the axonal connections of neurons can
branch extensively so that they have a divergence of output. This type of
connectivity means that most neurons receive thousands of synaptic inputs. They
integrate this complex input and compute a response:
convergence The synaptic input of many neurons on to one neuron
divergence The synaptic output of one neuron onto many neurons
temporal summation The additive effect of PSPs occurring close together in
time
spatial summation The additive effect of PSPs occurring together on nearby
parts of
the same cell
presynaptic inhibition Synaptic inhibition of an excitatory presynaptic terminal
causing a decrease in transmitter release
The ultimate outcome/goal of summation is to produce an action potential or train of
action potentials in the postsynaptic cell, to carry on signaling to the next level of the
neuronal network. The duration, rate and timing of action potentials in this output
train encode information about the spatiotemporal pattern of converging inputs.

** Electrophysiological experiment at a synapse **

These two slides demonstrate the relationship between a summed EPSP and the
spike it evokes in the postsynaptic cell.