Introduction

The cell is the microscopic fundamental working unit of all living things. Every living thing has
cells; bacteria, protozoans, fungi, plants and animals are the main groups of living things.

Early biologist saw cells as simple membranous sacs containing fluid and a few floating
particles. Today’s biologists know that cells are inconceivably more complex than this.
Therefore a strong knowledge of the various organelles and their functions is important to
physiologist. If a person’s cells are healthy then that person is healthy. All physiologic processes,
disease, growth and development can be described at cellular level. However, the extent to which
we can study a cell is determined by the resolution of the microscope. For instance, a light
microscope can resolve structures as close to 0.2µm, while an electron microscope can resolve
structures as close as 0.002µm

The advent of common access to fluorescent, confocal and other microscopy along with
specialized probes for both static and dynamic cellular structures further expanded the
examination of cell structure and function. Equally revolutionary advances in the modern
biophysical, biochemical and molecular biology techniques have also greatly contributed to our
knowledge of the cell.

Cells are enclosed by a lipid bilayer-a double layer of phospholipids that is impermeable to large
molecules and charged ions. The basic composition of the lipid bilaye is two layers of
phospholipids that arrange spontaneously, with the heads facing the extracellular fluid (ECF) and
intracellular fluid (ICF) (i.e., the water layers), and the fatty acid tails oriented toward the center,
the hydrophobic core of the membrane. Cholesterol is an inherent part of the membrane and
serves to siffen it. The plasm membrane is highly fluidy, with the consistency of olive oil, yet
this oil-like layer is an effective barrier to large, charged or hydrophilic molecules. Little
omevment across this membrane would be possible if it were not for the protein that float in this
lipid sea. The protein partially mobile within the bilayer, form channels and transporters which
regulate movement of large or charged molecules between the ECF and the inside of the cell.
This lipid bilayer with its integral proteins forms a semipermeable membrane through which
water, ions and nutrients can cross in regulated way.

The Cell membranes

The cell membranes is one of the basic component of a cell, others are the nucleus and the
cytoplasm. The cytoplasm is in turn made up of the cytosol and organelles. The cell membrane
generally referred to as plasma membrane is semipermeable allowing some substances to pass
through it and excluding others. The permeability of the cell membrane is varied because it
contains numerous regulated ion channels and other transport proteins that can change the
amounts of substances moving across it.

Structure of the cell membrane

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Although the chemical structures of membranes and their properties vary considerably from one
location to another, they have certain common features. The cell membrane is made up of lipids
and protein and generally about 7.5nm thick. The major lipids are phospholipids such as
phosphotidylcholine and phosphotidylethanolamine. In prokaryotes (i.e. bacteria in which there
is no nucleus), the membranes are relatively simple, but in eukaryotes (cells containing nuclei),
cell membranes contain various glycosphingolipids, sphingomyelin and cholesterol in addition to
phospholipids and phosphatidylcholine.

Many different proteins are embedded in the membrane. About 50% of membrane mass is
protein (integral and peripheral). The integral proteins pass through the membrane while the
peripheral proteins are stud on the inside and outside of the membrane.

Kinds/Functions of membrane proteins

The following are the kinds of membranes proteins

1. Cell adhesion molecule

2. Carrier protein
3. Ion channels
4. Pumps
5. Receptors
6. Enzymes

1. Cell adhesion molecules (CAMS).

They anchor or attach cells to their neighbours or to the basal laminas. The have unique structure
and signaling functions in embryonic development and formation of the nervous system/other
tissue, holding tissues together in adults, in inflammation/wound healing and in metastasis of
tumors. Many cell adhesion molecules pass through the cell membrane and are anchored to the
cytoskeleton inside the cell. Some bind to like molecules on other cells (hemophilic binding),
whereas others bind to non-self-molecules (heterophilic binding). Many bind to laminis a family
of large cross-shaped molecules with multiple receptor domains in the extracellular matrix.

Cell adhesion molecule can be divided into 4 broad families;

a.Integrins. Heterodimers that bind to various receptors

b. Adhesion molecules of the lgG superfamily of immunoglobulins

c. Cadherins, Ca2+-dependent molecules that mediate cell-to-cell adhesion by hemophilic

reactions

d. Selectins, which have lectin like domains that bind carbohydrate

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The cell adhesion molecules not only fasten cells to their neighbours, but also transmit signals
into and out of the cell. For example, cells that lose their contact with the extracellular matrix via
integrins have a higher rate of apoptosis than anchored cells and interactions between integrins
and the cytoskeletons are involved in cellular movement.

2. Carrier proteins: transport of substances down an electrochemical gradient by facilitated

diffusion. For example glucose crosses the cell membrane via a membrane protein i.e.
transporter. The process is still based upon diffusion, moving of a substance from an area of
higher concentration to a region of lower concentration, but this time the movement must occur
through an integral protein. Because the diffusion is determined by an integral membrane
protein, it is called facilitated diffusion. This facilitated diffusion is however limited by the
number of transporters present in the membrane.

The glucose transporters exist in several isoforms which facilitates movement of glucose across
the plasma membrane of skeletal muscle, cardiac muscle and adipose cells. The basic mechanism
of this transporter is simple. Glucose binds to the extracellular side of the membrane protein and
its binding causes a conformational, change in the transporter exposing the bound glucose to
intracellular space, glucose then diffuses down its concentration gradient into the intracellular
space. The more transporters there are in the membrane, the faster the glucose can move into the
intracellular space. Thus the glucose in the bottle of soda that you drank is transported from the
plasma into the extracellular space, then into intracellular fluid via membrane transport proteins
through facilitated diffusion. In the absence of transporters glucose cannot enter the ICF.

3. Ion channels; when activated permit the passage of ions into or out of the cell. Ions diffuse
across the membrane via ion channels. There are 3 basic types of ion channels; ungated, voltage
gated and the ligand gated.

i Ungated (leak)

This is always opened and the direction of movement of ions depends on electrochemical forces.
The ungated ion channel is the determinant of the resting membrane potential of a cell. The most
important channel for maintaining the resting membrane potential is the K+ leak channel. This
channel is always open at the resting membrane potential;-70mv. When this channel is open, K+
ions can move down their concentration gradient from the inside of the cell to the outside of the
cell. However as more positive ions accumulate on the outside of the cell, an electrical repulsion
occurs, slowing the movement of ions through the K+ leak channel. This movement of K+ ions
down a concentration gradient, but against an electrical gradient establishes an electrochemical
equilibrium at about -70mv.

K+ ions are attracted to negatively charged proteins within the cell, which limits their movement
through the K+ channel. In addition, the Na+/K+ ATPase contributes to the magnitude of the
resting membrane potential. Without the Na+/K+ ATPase, the resting membrane potential would
be about 5mv more positive. Certainly the distribution of other ions and the probability of other

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ion channel openings could affect resting membrane potential and does so in disease or because
of some drugs. However, in normal healthy person, the K+ leak channel is the primary
determinant of the resting membrane potential. The resting membrane potential is a potential
energy for opening of channels and generation of an action potential, the fastest form of
intercellular communication.

ii Voltage-gated

The open and closed state is determined primarily by the membrane potential (voltage) and the
change in membrane potential may open or close the channel. The Na+ channel is a typical
voltage-gated channel. The voltage-gated Na+ channel is a multi-subunit channel that allows Na+
to move outside the cell to the inside of the cell. The Na+ channel has an activation gate that
opens or closes the channel to the outside of the cell and an inactivation gate that opens and
closes the channel to the inside of the cell. Each of these gates is regulated independently. At
resting membrane potential, the Na+ channel will be closed with the activation gate blocking the
ion channel pore. The inactivation gate however will likely be open. In this state, the Na+
channel is closed, but ready to open. If positive charges accumulate near the Na + channel on the
interior surface of the membrane, the voltage sensor will cause a conformational change in the
protein ion channel. This change will increase the permeability of the activation gate opening. As
the membrane depolarizes (becomes more positive) from -70mv toward -55mv, the likelihood of
Na+ channel opening increases. a voltage of -55mv is generally considered a threshold voltage at
which most Na+ channel activation gates will open. The channel stays open for about 2
millisecond before the inactivation gate on the intracellular side closes, inactivating the channel.
Even though the activation gate is still open, no ions can pass through the protein pore. Over
time, several milliseconds usually, the inactivation gate will return to its open or resting state, the
activation gate will close and the channel will return to its original state- closed, but ready to
open. The time required for recovery from inactivation is important in action potential
conduction. Most ion channels behave similarly to the Na+ channel. The gates be shaped
differently or may have different voltage sensitivities or kinetics, but this basic pattern of
opening and closing is common to most ion channels.

iii ligand-gated channel

The channel contains a receptor. The state of the channel (open or closed) is influenced by the
binding of a ligand to the receptor. The ligands are usually hormones and the channels are called
ligand gated channels. Under most circumstances, the binding of the ligand opens the channel.
For instance during the transmission of impulse through the neuromuscular junction,
acetylcholine moves through the presynaptic membrane (membrane of axon terminal) and
reaches the synaptic cleft. Then, the acetylcholine molecules cause opening of sodium channels
in the postsynaptic membrane and sodium ions didduse into the neuromuscular junction from the
ECF.

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However, there is an exception to these three basic classes. The NMDA (N-methyl-D-aspartic
acid) is an exception because it is both voltage gated and ligand gated.

Voltage gated: The pore of the NDMA receptor is blocked by Mg2+, if E m is more negative than -
70mv. This Mg2+ block is removed if Em becomes less negative than -70mv. Thus the NDMA
receptor exhibits characteristics of a voltage-gated channel.

Ligand gated: glutamate and aspartate are the endogenous ligands for this receptor. Binding of
one of the ligands is required to open the channel, thus it exhibits the characteristics of ligand-
gated channel. If Em is more negative than approximately -70mV, binding of the ligand does not
open the channel (Mg2+ block related to voltage prevents). If E m is less negative than
approximately -70mV, binding of the ligand opens the channel (even though no Mg2+ block at
this Em, channel will not open without ligand binding).

The NDMA receptor is a non-selective cation channel (Na+, K+, and Ca2+ flux through it). Thus,
opening of this channel results in depolarization. Although the NDMA receptor is likely involved
in a variety of functions, the 2 most important are memory and pain transmission. With respect to
memory, NDMA has been shown to be involved in long term potentiation of cells, thought to be
an important component of memory formation. With respect to pain transmission, NDMA is
expressed throughout the CNS and has been proven in numerous studies to play a pivotal role in
the transmission and ultimate perception of pain.

Furthermore there are mechanically gated channels which are open by some mechanical
factors. Examples are channels present in the pressure receptors (Pacinian corpuscles) and the
receptor cells (hair cells) of the organ of corti and vestibular apparatus. When a Pacinian
corpuscle is subjected to pressure, it is compressed resulting in deformation of its core fibre. This
deformation causes opening of sodium channel and development of receptor potential. The
sound waves cause the movement of cilia of hair cells of corti (cochlea) which is the receptor
organ in the ear. The movements of cilia causes opening of potassium channels leading to the
development of receptor potential.

Ion Channels Diseases

Mutations in genes that encode the ion channels cause some disesaes such as;

a. sodium channel disesaes: muscle spasms and Liddle’s syndrome (dysfunction of

sodium channels in kidney resulting in increased osmotic pressure in the blood and
hypertension).

b. potassium channel diseases: disorders of the heart, inherited deafness and epileptic
seizures in new born.

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 c. chloride channel disease: renal stones and cystic fibrosis generalized disorder affecting
the functions of many organs such as lungs (due to exessive mucus), exocrine glands like
pancreas, biliary system and immune system.

4. Pumps: some membrane proteins engage in active transport or transport that that requires
adenosine triphosphate (ATP) or physiological work. The most ubiquitous of these is the Na+/K+
ATPase also known as the Na+/K+ pump. Recall that, the concentration of Na+ in the ECF is
much higher than in the ICF. At the same time, K+ is in higher concentration on the inside of the
cell and lower on the outside (ECF). The protein that helps to maintain this disequilibrium is the
Na+/K+ pump. An increase in intracellular Na+ allows binding of Na+ to the cytosolic side of the
Na+/K+ pump, a change in conformation and a release of Na+ to the extracellular space. K+ binds
to the extracellular face of the Na+/K+ pump and it is transported into the cell. However, both of
these ions are moving against their concentration gradient, so diffusion is not possible.
Movement of an ion against a concentration gradient, i.e., from an area of lower concentration to
an area of higher concentration requires energy in the form of ATP. For each ATP hydolysed,
three Na+ ions are pumped out of the cytosol and two K+ ions are brought into the cytosol from
the ECF. This imbalance contributes partially to the resting membrane potential. The Na +/K+
pump is expressed in nearly every cell of the body and is so active that its operation accounts for
30% of our resting energy use.

While the Na+/K+ pump is the most common active transporter, there are many others. In fact,
any time an ion is moved against a concentration an ATPase or ion pump will be required. Ca2+
is moved against a concentration gradient by a Ca2+ ATPase within the endoplasmic reticulum
(ER) membrane, or a different Ca2+ ATPase within the plasma membrane. H+ ion are similarly
moved by H+ ATPases. The basic principle to keep in mind is that movement of an ion or
molecule against a concentration gradient will always require energy.

Resting membrane potential

If we were to set up a voltmeter with two fine electrodes on the surface of a single axon, no
potential difference will be observed. However, if one electrode is inserted into the interior of the
cell, a constant potential is observed with the inside negative relative to the outside of the cell at
rest. A membrane potential results from separation of positive and negative charges across the
cell membrane. In neurons, the resting membrane potential is usually about -70Mv and it is close
to the equilibrium potential of K+. Thus the membrane potential is the electrical potential
difference which can provide energy for communication.

In order for a potential difference to be present across a membrane lipid bilayer, two conditions
must be met. First, there must be an unequal distribution of ions of one or more species across
the membrane (i.e. a concentration gradient). Two, the membrane must be permeable to one or
more of these ions species. The permeability is provided by the existence of channels or pore in
the bilayer; these channels are usually permeable to a single species of ions. The resting

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membrane potential represents an equilibrium situation at which the driving force for the
membrane-permeant ions down their concentration gradients across the membrane is equal and
opposite to the driving force for these ions down their electrical gradients.

In neurons, the concentration of K+ is much higher inside than outside the cell, while the reverse
is the case for Na+. This concentration difference is established by the Na+/K+ ATPase. The
outward K+ concentration gradient results in passive movement of K+ out of the cell when K+-
selective channels are open. Similarly, the inward Na+ concentration gradient results in passive
movement of Na+ into the cell when Na+-selective channels open. Because there are more open
K+ channels than Na+ channels at rest, the membrane permeability to K+ is greater.
Consequently, the intracellular and extracellular K+ concentrations are the prime determinants of
the resting membrane potential, which is therefore close to the equilibrium potential for K +.
Steady ion leaks cannot continue forever without eventually dissipating the ion gradients. This is
prevented by the Na+/K+ ATPase, which actively moves Na+ and K+ against their electrochemical
gradient.

Generation of an action potential

An action potential is a simple change in membrane voltage that propagates along a neuron,
muscle or any excitable cell. Electrical signaling between cells, with the elevtrical current carried
by ions instead of electrons is the fastest and most common form of intercellular communication.
An action potential can carry a signal along a distance in a very short time.

Depolarization of the resting membrane will move the resting membrane potential from -70mV
toward -55mV which is the threshold potential for Na+ channels. Once the first Na+ channels
opens, allowing Na+ ions into thr cell, the membrane potential will become even more
depolarized. Thus, opening even a few Na+ channels can begin a feed-forward event that
depolarizes the membrane and causes many Na+ channels to open. This is the beginning of an
action potential. The membrane actually depolarizes to +30mV in response to this increase in
intracellular Na+ ions. Once opened, the Na+ channels will inactivate and become refractory,
meaning they will fail to open again until they are reactivated. This is a short time, but a finite
time. New Na+ channels farther along the neuron can open, but the ones already opened will
become unavailable. This phenomenon moves the action potential to new portions of the neuron
and gives the action potential a direction. The initial section of the neuron, where the action
potential began, has reached 0 mV to +30 mV, a voltage range at which voltage-gated K+
channels can open. The electrochemical gradient is favorable for K+ flow out of the cell into the
extracellular space. Once again, the opening of K+ channels proceeds down the neuron as the
membrane potential enters the voltage range of these channels, 0 mV or more positive. The
movement of positive charges out of the cell restores the resting membrane potential of -70mV
before the K+ channels close. Only a small number of Na+ and K+ must cross the membrane to

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create the necessary change in voltage, and these are returned to respective spaces by the Na +K+
pump.

4. Receptors

Not all intercellular signals are as fast and discrete as neuronal action potential. Hormones,
chemicals released by cells into the blood supply can also bind to receptors and cause signal
changes in cellular function in tissues far distant to the cells that released them. This type of
chemical signaling takes longer to have its effect, but the eefect are generally longer-lived,
lasting from minutes to days instead of milliseconds. The most important thing to remember
about hormone signaling is that the hormone will bind to a receptor and it is the receptor that
determines the intercellular response to binding. We can use epinephrine also known as
adrenaline to illustrate this.

Epinephrine is released from cells of the supra renal glands. Once in the blood supply,
epinephrine can bind to β-adrenergic receptors, located on skeletal muscle. β-adrenergic
receptors are part of a large family of membrane receptors called guanine nucleotide-binding
protein (G-protein) coupled receptors, with seven transmembrane loops that link to intracellular
heterotrimetric G-proteins α, β and ϒ. These proteins are called G-proteins because they are
inhibited by a bound guanosine diphosphate (GDP) molecule.

When epinephrine binds to this receptor, it changes the conformation of the transmembrane
protein. The conformational change reduces the binding affinity of GDP, which releases and is
replaced by guanosine triphosphate (GTP), thereby activating and releasing the α-subunit. The
α-subunit detaches and binds to an enzyme, adenylate cyclase, attached to the inner leaflet of he
plasma membrane. Adenylate cyclase converts ATP to cyclic adenosine monophosphate
(cAMP), a signaling molecule. cAMP binds to protein kinase A, which can phosphorylate (add a
phosphate group to) proteins. Phosphorylation is a common switch for regulating cellular
proteins. Protein kinase A can phosphorylate many proteins including glycogen phosphorylase,
the enzyme that initiates the hydrolysis of intramuscular glycogen into glucose. Thus,
epinephrine binding to a β-adrenergic receptor on skeletal muscle will increase the amount of
free glucose available for energy.

Furthermore, epinephrine can also bind to a different receptor, an α-adrenergic receptor. It binds
with less affinity than the β-receptor, but it can activate α-receptors. The α-receptors are also G-
protein coupled receptors, but the G-proteins are different and the intracellular action is different.
When epinerphrine binds to an α-receptor, the conformation change and substitution of GTP for
GDP occurs as with the β-adrenergic receptor. The activated subunit is αq, and it binds to a
different membrane-bound enzyme-phospholipase C. Phospholipase C cleaves the phospholipids
of the membrane itself to create two signaling molecules: IP 3 and diacyglycerol. IP3 binds to
receptors on the endoplasmic reticulum or sarcoplasmic reticulum (SR) and causes the release of
Ca2+, itself a signaling molecule. Diacylglycerol activates a kinase, protein kinase C (PKC),

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which will phosphorylate proteins. While PKC can phosphorylate many proteins and initiate
changes in gene expression, the protein target we look at is the L-type Ca2+ channel just like the
one found in neurons. When phosphorylated by PKC, this channel increase its conductance, thus
allowing more calcium to enter the cell. Activated α-receptors, well distributed in smooth
muscle, will increase smooth muscle contraction by two methods, well distributed in smooth
muscle, will increase smooth muscle contraction by two methods: an increase in intracellular
Ca2+ from the action of IP3, and a similar increase resulting from greater flow of Ca 2+ ions
through the L-type Ca2+ channel. During your run, this will mean smooth muscle contraction of
the venous vasculature, which increases the blood flow into your heart. One hormone, therefore
can have multiple actions, depending on the receptor to which it binds.

Another class of membrane protein receptor protein, from a very different family are the receptor
tyrosine kinases. Thee receptors are simple dimers of α helices within the plasma membrane and
as such caanot create a conformational change in their basic structure. When a hormone binds to
one of the receptor tyrosine kinases, the two subunits of the receptor phosphorylate each other on
tyrosine residues of the helices. This dimerized receptor then begins a complex series of signal
transduction beginning with membrane associated proteins and ending at the nucleus. An
example of this type of receptor is the insulin receptor. When you finish a race and drank a bottle
of soda it was the binding of insulin to tyrosine kinase receptors that allowed glucose
transporters to be moved to the plasma membrane. In this way, glucose could get from the blood
supply into the cell for metabolism and energy production.

Some hormones or neurotransmitters can cross the plasma membrane freely: the most recently
discovered class of signaling molecules are gases, which can freely cross a plasma membrane.
Several gasous molecules have been attributed with signaling properties, including CO 2 and H2S,
but NO (nitric oxide) is widely studied. Nitric oxide is enzymatically formed by NO synthase
from the amino acid, arginine and is a lipophilic gas. Being lipophilic, it can diffuse freely
through plasma membranes, but its half-life is so short (seconds) thst its effect are limited to
tissues in the immediate area of its synthesis. For example, endothelial cells that line the interior
of blood vessels synthesize NO, which diffuses into the blood and from there into the smooth
muscle surrounding the blood vessel. Inside the smooth muscle cell, NO converts GTP into
cGMP, activating protein kinase G (PKG). This protein kinase ultimately inhibits myosin and
prevents muscle contraction, thus allowing vasodilation. Injection of inhibitors of NO synthase
prevents the erection normally produced by stimulation of the pelvic nerve in experimental
animals. Thus it seems clear that NO plays a prominent role in the production of erection. Thus,
the drugs sildenafil, tadalafil and verdenafil all inhibit the break down of cGMP by
phosphodiesterases and have gained world-wide fame for the treatment of impotence.

Some hormones bind to receptors inside the cell; whereas hormones derived from amino avids
like epinephrine, cannot cross plasma membrane, steroid hormones have cholesterol as their
parent molecule and cholesterol is itself an important component of the plasma membrane. There
fore, steroid hormones can freely pass into a cell and bind to receptors either in the cytoplasm or
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nucleus. The receptor-hormone complex functions as a transcription factor, stimulating gene
transcription. Steroid hormones, which include testosterone, estrogen, progesterone, cortisol and
aldosterone, causes changes in gene expression and therefore the production of new proteins.
The process takes longer than signal transduction through a G-protein coupled receptor (hours
rather than minutes) but the creation of new protein that occurs as a result will be a much more
sustained response. Thus steroid hormones can regulate cellular function for hours, days and
weeks.

Note that the lipid component of steroid hormone make them soluble in plasma membrane but
insoluble in plasma. Thus steroid hormone is carried by proteins in the circulating blood. At low
concentrations, steroid hormones remain bound to their carrier proteins. At higher concentrations
e.g., following release from their tissue of origin, they will exist in a dynamic equilibrium with
carrier proteins and will unbind periodically allowing their passage cross the membrane

If you become thirsty during as exercise. An increase in apparent K+ plasma concentration,

which occurs with dehydration is sensed by cells of the adrenal glands, which release the steroid
hormone aaldosterone. Aldosterone circulates in the blood and has its target in the tubules of the
kidney. Once inside the cells of the kidney tubule, aldosterone causes an increase in Na + ion
channel expression, whuch results in concentration of urine, providing a means for conservation
of water. The end result is that you produce less urine and maintain fluid balance.

SYNAPTIC TRANSMISSION

Neuromuscular Junction (NMJ).

The synapse between the axon of an alpha motor neuron and a skeletal muscle fibre is called the
neuromuscular junction. The terminals of alpha-motor neurons contain acetylcholine (Ach), thus
the synaptic transmission at the NMJ is one example of cholinergic transmission.

Sequence of events

1. The action potential Travelling down the motor neuron depolarizes the presynaptic membrane.

2. this depolarization opens the voltage-gated Ca2+ channels in the presynaptic membrane,
resulting in Ca2+ influx into the presynaptic terminal.

3. the rise in Ca2+ causes synaptic vesicles to release their contents, in this case Ach. The amount
of neurotransmitter release is directly related to the rise in cytosolic Ca 2+ , i.e., the more Ca2+ that
enters, the more neurotransmitter that is released

4. Ach binds to a nicotinic receptor located on the muscle membrane (N M receptor). The NM
receptor is a non-selective monovalent cation channel (both Na+ and K+ can traverse). Given that

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Na+ has a much greater net force depolarization occurs. This depolarization is called an an end
plate potential (EPP). The magnitude of EPP is directly related to the amount of Ach released.

5. The resulting depolarization opens fast Na+ channels on the muscle membrane (sarcolemma)
cuasing an action potential in the sarcolemma. Under nirmal circumstances, an action potential in
the motor neuron releases enough Ach to cause an EPP that is at least threshold for the action
potential in the skeletal muscle cell. In other words, there is one-to-one relationship between the
action potential in motor neuron and an action potential in the skeletal muscle.

6. The action of Ach are terminated by acetylcholinesterase (AchE), an enzyme located on the
postsynaptic membrane that breaks down Ach into choline and acetate. Choline is taken back
into the presynaptic terminal (reuptake), hence providing substrate for re-synthesis of Ach.

Other cholinergic synapses

i Neuronal nicotinic (NN) receptors: outside of the CNS, these primarily reside in autonomic
ganglia. Recall that pre-ganglionic neurons are cholinergic and these fibres synapse on nicotinic
receptors in the ganglia.

ii Muscarinic receptors: muscarinic receptors are G-protein coupled receptors. These reside in
target tissues innervated by parasympathetic postganglionic neurons

Synapses Between Neurons

Generally, synaptic potentials produced are excitatory or inhibitory and are produced by ligand-
gated ion channels. Some other important aspects associated with these synapses are:

 Synapses are located on the cell body and dendrites

 The current produced at these synapses travel along the dendritic and cell body
membranes.
 The axon hillock-initial segment region has a high density of fast Na + channels and is
the origin for action potential of the axon.
 The closer the synapse is to this region, the greater its influence in determining whether
an action potential is generated.
 If the sum of all inputs reaches threshold, an action potential is generated and conducted
along the axon to the nerve terminal.

Excitatory postsynaptic potential (EPSP)

EPSP is excitatory if it increases the excitability of the postsynaptic neuron, i.e., it is more likely
to fire an action potential.

 It is primarily the result of increased Na+ gate

 It is similar to the EPP found at the neuromuscular junction

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Important receptors that produce EPSP include;

- Nicotinic: endogenous ligand is Ach and include NM and NN

- Non-NMDA (N-methyl-D-aspartic acid): endogenous ligands are glutamate and aspartate

(excitatory amino acid transmiiters), and Na+ gate is increased when they bind

NMDA: Endogenous ligands are excitatory amino acids and it is a non-selective cation channel

Inhibitory postsynaptic potential (IPSP)

IPSP is inhibitory if it decreases the excitability of the postsynaptic neuron, i.e., it is less likely to
fire an action potential.

It is primarily the result of increased Cl- gate

Important receptors that produce:

GABAA&C: Endogenous ligand is GABA (gamma-aminotryic acid).

Glycine: Endogenous ligand is glycine:

Electrical synapses

 In contrast to chemical synaptic transmission, there is a direct flow of current from cell to
cell.
 This cell-to-cell communication occurs via gap junctions; because the cells are
electrically coupled, there is no synaptic delay.
 Cardiac and single-unit smooth muscle cells have electrical synapses

Clinical applications of decreased neuronal excitability/conduction

Clinical signs could include: weakness; ataxia; hyporeflexia; paralysis; sensory deficit. Possible
causes include the following

Clinical applications of increased neuronal excitability/conduction

Clinical signs could include: hyperreflexia, spasms, muscle fasciculations, tetany, tremors,
paresthesias, and convulsions.

For instance when you work out and you become thirsty, there is an increase in apparent K+
plasma concentration, which occurs with dehydration. This is sensed by cells of the adrenal
glands which release the steroid hormone aldosterone. Aldosterone circulates in the blood an has
as its target the tubules of the kidney. Once inside the cells of the kidney tubule, aldosterone
causes an increase in Na+ ion channel expression, which results in concentration of

12
urine,providing a means for conservation of water. The end result is that you produce less uribe
and maintain fluid balance.

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