LECTURE ON;

ION TRANSPORT,
ACTION POTENTIAL &
TRANSMISSION

DEPARTMENT OF MEDICAL
REHABILITATION,FACULTY OF HEALTH SCIENCES,
UNIVERSITY OF NIGERIA ENUGU CAMPUS

JULY, 2021
OUTLINES
INTRODUCTION
NEURON STRUCTURE AND FUNCTION
TRANSPORT MECHANISMS;
Active transport and
Passive transport
FACTORS CONTRIBUTING TO ION MOVEMENT
ION TRANSPORT
TYPES OF ION CHANNELS
RESTING MEMBRANE POTENTIAL
ACTION POTENTIAL AND PROPAGATION
SYNAPTIC TRANSMISSION
CLINICAL CORRELATION
CELL RECAP
INTRODUCTION
• Cell membrane is responsible for the maintenance of
the intracellular environment from the extracellular
environment
• In neurons and other excitable cells, regulation of the
ionic environment is also crucial for the development
and maintenance of the electrical signalling system.
• These system is composed of two basic elements;
lipid bilayer and two classes of macromolecule
proteins.
• Ion channels are membrane proteins that give rise to
selective permeability, whereas active transporters
create and maintain ion gradients.
INTRODUCTION
• Resting neurons generate a negative potential,
termed the resting membrane potential

• The primary electrical signal generated by neurons

is called the action potential.

• The same mechanism of generation of action

potential is responsible for propagation of action
potentials along the length of the axons.
NEURON STRUCTURE AND FUNCTION
• The animal nervous system is
composed of two cell types:
neurons and
support cells.
Neurons produce and conduct
electrochemical signals,
while support cells aid the
neurons in a variety of ways.
• Neurons are distinguished by their
ability to respond to external
stimuli by altering their membrane
potential. This property is referred
to as electrical excitability.
 NEURON STRUCTURE AND FUNCTION
• Neurons are triggered by stimuli, chemical and
electrical, and these signals are transmitted along
the length of the axon by briefly altering the
membrane potential.

• The resting membrane potential (often referred to

as resting potential) for a typical neuron is -70 mV.

• This indicates that the inside of the cell is negatively

charged compared to the outside of the cell.
IONIC CONCENTRATION OF NEURON
 FUNCTIONS OF NEURON
• The cell body: containing the
nucleus, is the metabolic center
of the cell.
• The dendrites receive
electrochemical signals from
other neurons.
• The axon transmits the nerve
impulse away from the cell body
toward the terminal bulb, which
makes contact with a target cell.
• Ion transport through cell
membranes is fundamental for
many of the basic neuronal
functions
TRANSPORT MECHANISMS
• The plasma membrane functions to separate the cell
from its surroundings; additionally, it regulates the
transport of material in and out of the cell.
• Transport is the movement of solutes across a
membrane, and in most cells this includes
membranes within the cell as well as the plasma
membrane.
• There are several different mechanisms for the
transport of solutes:
ACTIVE TRANSPORT AND

PASSIVE TRANSPORT
 ACTIVE TRANSPORT
• Movement of solute acoss a memebrane against an
electrochemical gradient.

• Carrier-mediated active transport;

Primary
Secondary
• Vesicular transport

• Uphill Transport; Requires metabolic energy; exhibits

saturation kinetic.
 PRIMARY ACTIVE TRANSPORT
• This antiport transport system is responsible for
maintaining the high K+ and low Na+ concentration
inside the cell.

• E.g Na-K pump which uses as its carrier, membrane-

bound ATpase.
• The carrier ATPase is a protein made up of four
subunits, termed 2alpha and 2beta units.
• At the cytoplasmic side, the alpha subunit has
ATPase activity and binding sites for Na+, ATP
molecule and phosphate
• At the extracellular site, it has binding sites for 2K+.
 PRIMARY ACTIVE TRANSPORT
Mechanism:
3 Na+ and ATP molecule bind
with the carrier on the inside
of the cell, hydolysis of ATP
occurs giving rise to ADP and
Pi.
The Phosphate group is bond
to aspartate acid residue of
the alpha subunit.
The phosphorylation of the
alpha subunit causes a
change in the conformation of
the carrier, which leads to the
movement of 3Na+ out of the
cell.
 PRIMARY ACTIVE TRANSPORT
• Mechanism contd:
2 K + bind to the outside
of the alpha subunit
and this leads to the
hydrolysis of the aspartic
acid-phosphate bond
This in turn causes
another conformational
change in the alpha
subunit that lets in 2 K+.
other examples; Ca+
pump and H+ pump.
SECONDARY ACTIVE TRANSPORT
• Depends on primary active transport

• The primary active transport of the Na+ out of the

basal and basolateral membranes of the proximal
tubules of the nephron and small intestine

• leads to a facilitated diffusion of Na+ from lumen

into the cells

• Either a symport or an antiport

 VESICULAR TRANSPORT
• Large macromolecules such as protein molecules
enter by pinocytosis

• Large particles such as bacteria enter by

phagocytosis.
PASSIVE TRANSPORT
• Movement of solutes across a membrane down a
concentration gradient, from a region of higher
concentration to one of lower concentration.

• Examples of passive transport include

Simple diffusion,
Osmosis
facilitated diffusion
and ion channels.

• Transport is downhill; Does not require metabolic

energy;
SIMPLE DIFFUSION
• Unassisted diffusion of a solute across the lipid
bilayer of a membrane.

• The solute must be moving down a concentration

gradient with a negative free energy change (-
deltaG).

• Also, the membrane must be able to accommodate

the solute and allow it to traverse.

• The size and polarity of a particular solute determine

if the membrane is permeable to that solute
OSMOSIS
• Biological membranes are permeable to water but
not to ions or small polar organic molecules.
• Due to this difference in permeability, water moves
across a membrane from a region of low solute
concentration to a region of high solute
concentration. This passive transport of water is
called osmosis
• Hypertonic solution

• Hypotonic solution

• Isotonic solution
FACILITATED DIFFUSION
• Protein-mediated transport of solutes across a
membrane and down the electrochemical gradient
by a carrier protein

• Carrier proteins mediate transport by binding on

one side of the membrane and then undergoing a
conformational change that delivers the solute to
the other side of the membrane.

• One of the best understood carrier proteins is the

glucose carrier protein GLUT1
FACTORS CONTRIBUTING TO ION
MOVEMENT
• Concentration gradient

• Electrical gradient

• Transporter activity
 ION TRANSPORT
• Lipid bilayers are not permeable to charged ions.
Nevertheless, the movement of ions in and out of
the cell is critical for their normal activity.
• Ions do not pass through the plasma membrane by
simple diffusion rather their transport is mediated by
protein-lined channels termed ION CHANNELS.
• Ion channels provides a passage through which
ions can transverse the membrane and is extremely
selective
• Ion transport through these channels is an example
of passive transport because energy is not required
and the movement of ions is driven by their
concentration gradient.
 ION TRANSPORT
• Passive transport is also called facilitated diffusion.
• In the simplest form, ion channel is always open and
the flow is bidirectional.
• Many ion channels are gated, regulated to be in
either the open/closed conformation
• However extrinsic factors such as;
Changes in membrane potential
or the binding of small regulatory
molecules(extracelular neurotransmitter or
intracellular second messenger),
dictate whether channel protein will be in an open or
“gated” State or closed State.
 ION TRANSPORT
• There are
mechanisms by
which an ion channel
may open or close:
A mechanical gating
Changes in the
membrane potential
Interaction of the
channel with a
hormone or
neurotransmitter.
TYPES OF ION CHANNELS
• Voltage-gated ion channels

• Mechano-Senstive channels

• Ligand gated channels

• Intracellular channels and

• Connexins and Pannexins

VOLTAGE-GATED CHANNEL
• Super family of ion channels that include Na, Ca
and K channels.
• They are macromolecular complexes in the lipid
membrane containing the auqeous pores and
voltage-sensors
• A part of the pore know as ionic selective filter is
narrow enough to distinguish among Na+, K+ and
Cl+.
• The voltage sensor is the charged component that
senses the electrical field in the membrane and
drives conformational changes, leading to opening
and closing of the gates
VOLTAGE-GATED CHANNEL
• The voltage dependent opening of ionic channel is
known as activation

• After few millionseconds, the channel inactivated

and the flow of ion is blocked again

• After inactivation, the channel returns to its resting

state until the next depolarization triggers the whole
process again
VOLTAGE-GATED Na+ CHANNEL
• Consist of the pore forming alpha subunit associated
with auxillary beta subunit
• The alpha subunit is sufficient for functional
expression, but the channel gating is modulated by
the beta subunit
• In some cells, these channels are are solely
responsible for the rapid and regenerative upstroke
of action potential
• In others, they act in conjunction with voltage-gated
Ca2+ channels to depolarize cells.
• Also expressed in non-excitable cells at lower level,
where their physiologic role is unclear
VOLTAGE-GATED Ca2+ CHANNEL
• Purification of the channel has identified five
subunits, a large alpha 1 subunit and four smaller
auxillary subunits; alpha 2, beta, gamma and delta.
• There are 2 groups:
Low-voltage activated Cav channels: Require
only weak membrane depolarization to open. Are
activated by relatively hyperpolarizedmembrane
potentials.
Because of its stron inactivation properties, these
channels are often called transient or T-type
channels.
VOLTAGE-GATED Ca2+ CHANNEL
High-voltage activated cav channels: Requires
moderate to strong membrane depolarization.
• The Ca2+-selectivity and voltage-sensitivity of
these channels are common features between
two major groups which are separated by their
sensitivity to changes in membrane potential.
• Serves two functions:
Electrogenic and
Regulatory.
• The most important process regulated by these
channels is the release of neurotransmitters at
synapses.
VOLTAGE-GATED Ca2+ CHANNEL
• LVA channels exhibit rapid and complete voltage
dependent inactivation and are unlikely candidates
to promote sufficient Ca2+ influx. The major
function is electrogenic; at the resting potential
• Hva channels inactivate incompletely and are
solely responsible to keeping the cells depolarized
for a prolonged period. Such action potentials drive
Ca2+ dependent processes such as
neurotransmitter.
• In accordance with this, HVA channels are found at
synaptic endings and Na+ channels in axons.
MECHANO-SENSITIVE CHANNELS
• Ion channels responding to changes in mechanical
forces on the cell membrane.
• These channels are involved in detection and
transduction of external mechanical forces into
electrical and/or chemical intracellular signals.
• Mechano-sensitive ion channels are involved:
Sense of hearing

Regulation of blood pressure and Cell volume,

Stimulation of muscle and bone development.

 EXTRACELLULAR LIGAND-GATED
CHANNELS
• Also known as neurotransmitter-controlled channels.
• Activation of ligand-gated receptor channels depends
on the binding of a ligand to the extracellular domain of
these receptors
• Termination of activities of these channels requires
removal of the ligand through a specific pathway for
ligand degeneration and uptake
• During prolonged receptor occupancy, the
conductance through ligand-gated receptor channels
decrease in a process called desensitization;
analogous to inactivation of voltage-gated channels
EXTRACELLULAR LIGAND-GATED
• Two classes: CHANNELS
Excitatory cation-selective channels, operated
by;
Acetylcholine
Glutamate
5-hydroxytryptamine(5-HT)
Adenosine 5’-triphosphate(ATP).
Inhibitory anion-selective channels, activated
by:
GABA and
Glycine
EXTRACELLULAR LIGAND-GATED
CHANNELS
• The 5-HT3, GABA and glycine receptor channels
posess structural features similar to the nicotine
acetylcholine-activated receptor channel, and they
are grouped as one family, known as ligand-gated
ion channels of the cys-loop family.
NICOTINIC ACETYLCHOLINE AND 5-
HYDROXYTRYPTMINE RECEPTORS ARE CATION
CHANNELS
• nAChRs critical for neuromuscular coupling; upon
binding of acetylcholine, nAChR channels open to
allow Na+ to flow through the channel.
• The resulting plasma membrane depolarization
opens Cav channels and initiates Ca2+ release
from sarcoplasmic reticulum through ryanodine
receptor channels.
• In skeletal muscle, activation of voltage-gated
Ca2+ influx in the T-tubule plasma membrane is
the primary signal that activates intracellular Ca2+
release channels and ultimately stimulates
muscular contraction.
NICOTINIC ACETYLCHOLINE AND 5-
HYDROXYTRYPTMINE RECEPTORS ARE CATION
CHANNELS
• Although found in most parts of the brain, their
functional significance is not well-activated.
• Both Ca2+ influxes through activated nAChRs and
Ca2+ potentiation probably account for the
physiologic actions of these channels.
• Calcium potentiation is a process in which Ca2+
influx through one channel regulates the efficacy of
other ligand-gated channels, leading to the
modulation of membrane excitability in neurons, as
well as their ability to integrate paracrine and
synaptic signal.
NICOTINIC ACETYLCHOLINE AND 5-
HYDROXYTRYPTMINE RECEPTORS ARE CATION
CHANNELS
• Furthermore, nAChR-dependent Ca2+ signals
enhance protein-kinase activity in myotubules,
leading to phosphorylation of the nAChR gamma
subunit.
• Because this process is dependent on Ca2+ influx,
it can be considered as autoregulation of
phosphorylation by n AChRs.
• Recent results, indicate that point mutation in this
receptor may abolish:
Desensitization
increase the affinity for agonists and
NICOTINIC ACETYLCHOLINE AND 5-
HYDROXYTRYPTMINE RECEPTORS ARE CATION
CHANNELS
and convert the effects of competitive antagonists
into agonist responses.
• Such mutations also occur spontaneously in
humans and may be involved in diseases such as
congenital myasthenia or frontal-lobe epilepsy
• The 5-HT3 receptor is expressed throughout the
central and peripheral nervous system and
mediates a variety of physiological functions:
Fast excitatory synaptic transmission in neocortical
interneurons, amygdala and visual cortex
Also present on presynaptic nerve terminals, where
they contribute to the control of neurotransmission
GABA and Glycine Receptors
Are Anion-Permeable Channels
• Gaba is major inhibitory neurotransmitter in the
vertebrate CNS that acts through two different
receptor channels, GABAA and GABAC, in addition
to G protein-coupled GABAB receptors.
• In Immature neurons, however, GABA-mediated
responses are often depolarizing, caused by CL-
efflux due to the high intracellular CL-conc.
• These receptors are targets for many drugs in wide
clinical use including; benzodiazepines,
barbiturates, neurosteroids, ethanol, and general
anesthetics which increase their conductance via
GABA channels
GABA and Glycine Receptors
Are Anion-Permeable Channels
• Glycine is the main inhibitory neurotransmitter in the
CNS, particularly in the spinal cord and the brain
stem where as GABA is more abundant in rostral
parts of the CNS.

• At the synapses, glycine are clustered at the

postsynaptic membrane directly opposite the
presynaptic release sites and are linked to the
subsynaptic cytoskeleton by gephyrin.
GLUTAMATE CHANNELS
• some are both voltage and ligand gated
• major excitatory neurotransmitter in the CNS
• acts through many ionotropic and metabotropic
receptors
• iGluRs are encoded by 18 genes that assemble to
form four major subtypes:
amino-3 -hydroxy-5-methyl-4-isoxazole propionic
acid(AMPA).
kainate
N-methyl-D-aspartate(NMDA).
Delta receptors
GLUTAMATE CHANNELS
• NMDA channels exhibit a different excitation
behaviour than those not activated by NMDA.
• NMDA receptors:
requires application of L-glutamate and glycine
and only become fully activated by glutamate after
Mg2+ block has been relieved by membrane
depolarization.
exhibits low-binding affinity sites for Ca2+, which
results in low selectivity for cations
• Synaptic plasticity are dependent on the behaviour
of NMDA receptor channels and Ca2+ influx through
the channels.
 P2X Receptors
• Seven purinergic receptors identified

• They are the most recently discovered membrane ion

channels.

• Ca2+ is a charge carrier through these channels,

although the permeability of Ca2+ versus Na+ varies
widely among different cell types.

• Thus can serve as Ca2+ influx channels.

• Also facilitate calcium influx indirectly, by depolarizing

cells and activating Cav.
 P2X Receptors
• In addition to stimulating intracellular Ca2+ signals,
the paracrine actions of ATP on purinergic receptors
can generate the cell-to-cell spread of Ca2+ signals
in glial cells in the absence of gap-junctional
communication.

• P2X receptors are widely expressed in many tissues

and are shown to play key roles in various
physiological processes, such as nerve transmission,
pain sensation, and various inflammatory responses.
 ENaC/ DEGENERIN FAMILY OF
CHANNELS
• Encodes Na+ channels involved in various cellular
functions.
• This superfamily channels include
ENaC,
Acid-sensing ion channels,
FMRF-amide activated channels,
DEG of Caenorhabditis elegans
and orphan channels
• In contrast with Nav channels, ENaC is localized in
apical membrane of polarized epithelial cells,
where it mediates Na+ transport across tight
 ENaC/ DEGENERIN FAMILY OF
CHANNELS
• The EnaC-mediated reabsorption of Na+ occurs in
the epithelial linning of the distal part of the kidney
tubule, the alveolar epithelium, and the distal colon
epithelium.
• Similar to other ENaC/DEG superfamily members,
ENaC is very sensitive to amiloride
• ASICs are directly activated by a drop in extracelluar
PH.
• The functional role of ASICs in the PNS was linked
with nociception, perception of sour taste, modulation
of synaptic transmission and mechanosensory
transduction.
ENaC/ DEGENERIN FAMILY OF
CHANNELS
• The functional role of ASICs in the PNS was linked
with nociception, perception of sour taste,
modulation of synaptic transmission and
mechanosensory transduction.

• These channels are also expressed in the brain but

their function in the central neurons is still not
clarified.
INTRACELLULAR/EXTRACELLULAR
MEMBRANE
• The expression of ion channels is not limited to the
plasmamembrane
• Two types of channels are expressed in the
ER/Sarcoplamic reticulum and nuclear membrane
ryanodine receptor channels(RyRs) and
Inositol 1, 4, 5-triphosphate receptor
channels(IP3Rs)
• RyRs provide an effective mechanism for
transduction and translation of electrical signals
inside the cells
INTRACELLULAR/EXTRACELLULAR
MEMBRANE
• where as IP3Rs are activated by two classes of
plasma membrane receptors known as Ca2+-
mobilizing receptors,
their activation is independent of the electrical status
of cells and represents the major pathway for Ca2+
signalling in non-excitable cells and also excitable
cells including neurons.
Activation of IP3Rs leads to stimulation of voltage-
insensitive Ca2+ channels expressed on the plasma
membrane and this process is known as
Capacitative Ca2+ entry.
Voltage-Gated Ca2+ Influx Activates
Ryanodine Receptors
• RyRs were originally identified as Ca2+ release
channels expressed in the sarcoplasmic reticulum
in skeletal muscle fibres and cardiac myocytes
where they play a role in excitation-contraction
coupling
• Mammalian tissues express three isoforms:
• RyR1 is expressed predominantly in skeletal
muscle
• RyR2 is expressed in cardiac muscle
• RyR3 has a wide tissue distribution including non-
excitable cells.
Voltage-Gated Ca2+ Influx Activates
Ryanodine Receptors
• Largest known ion channels and are susceptible to
many different modulators, including cystolic
calcuim, membrane potential and several
intracellular messengers.

• As in the regulation of IP3Rs, intracellular Ca2+ is a

major regulator of RyRs.

• The ability of Ca2+ to stimulate its release from the

endoplasmic /sarcoplasmic reticulum via RyRs is
known as Ca2+- induced Ca2+ release
RESTING MEMBRANE POTENTIAL
 ACTION POTENTIAL
• A distinct change in
membrane potential
that occurs in
response to a
stimulation.
• An action potential
can be classified into
four distinct phases
that correlate with
changes in sodium
ion and potassium
ion permeability.
 ACTION POTENTIAL
• The four phases of an action potential are:

Resting,
Depolarization,
Repolarization, and
Hyperpolarization.

• The resting neuron has a membrane potential of -70

mV, which is maintained by the potassium leak
channels.
 ACTION POTENTIAL
• Depolarization:
A reduction in the difference in charge across the
membrane.
The stimulation of the neuron must depolarize the
membrane beyond the threshold level (-50 mV).
If the initial depolarization does not exceed the
threshold level, then the action potential will not
proceed and the membrane potential will return to
the resting potential.
If the threshold is exceeded, then the voltage-gated
sodium channels are opened and there is a rapid
inflow of sodium ions, reversing the membrane
potential from a negative value to a positive value.
 ACTION POTENTIAL
Depolarization typically occurs in less than one
millisecond, then the voltage-gated sodium
channels are inactivated.
Depolarization triggers the voltage-gated
potassium channels to open, and the third phase
of the action potential (i.e. repolarization) is
initiated.
• Repolarization:
The voltage-gated potassium channels open and
there is an efflux of potassium ions that restores
the negative charge to the interior of the cell.
The voltage-gated potassium channels are slow to
close after the change in membrane potential.
 ACTION POTENTIAL
• Hyperpolarization:
Increasing the membrane potential beyond the level
of the resting potential .
The potassium leak channels then reestablish the
resting membrane potential.

During this period, the sodium channels are restored

to the active, but closed, state and this portion of the
axon is ready to repeat the action potential in
response to further stimulation.
 ACTION POTENTIAL PROPAGATION
• The action potential
occurs over a relatively
small area of the axon
membrane.
• It spreads along the full
length of the axon
through waves of
depolarization and
repolarization that travel
along to the terminal
bulb
 ACTION POTENTIAL PROPAGATION
• The action potential
spreads because the
region that has just
produced an action
potential is refractory for
a brief period of time,
but the adjacent region
slightly depolarizes,
triggering a new action
potential
SYNAPTIC TRANSMISSION
 SYNAPTIC TRANSMISSION
• Synaptic transmission is the signaling that occurs
between cells across the synaptic cleft.
• In most synapses this is mediated by the release of
chemical signals from the presynaptic cell that
crosses the synaptic cleft, which triggers a change
in the postsynaptic cell.
• The action potential of the presynaptic cell triggers
the release of neurotransmitters into the synaptic
cleft via regulated exocytosis.
• Once in the synaptic cleft, the neurotransmitters
bind to distinct receptors on the surface of the
postsynaptic cell and initiate a change in membrane
potential.
 SYNAPTIC TRANSMISSION
• Through this process of synaptic transmission, an
action potential in the presynaptic cell is transmitted
to the postsynaptic cell via a chemical signal.
 NEUROTRANSMITTER RECEPTORS
• There are two distinct types of neurotransmitter
receptors that can trigger a change in the
membrane potential of a postsynaptic cell:

Ligand-gated ion channelsand

G-protein linked receptors

• In the absence of the neurotransmitter, the ligand-

gated ion channel is closed to the flow of ions.
Restated, the pore that ions flow through is blocked
or gated.
 NEUROTRANSMITTER RECEPTORS
• When the receptor binds to the neurotransmitter, a
conformational change is induced that allows the
gate to open and ions to flow through the channel
• The flow of ions is rapid and brief, resulting in a
change in the membrane potential.
• Once the ligand has bound to the receptor, it
rapidly dissociates from it and the channel returns to
the closed state.
• Termination of the flow of neurotransmitters ensures
that the postsynaptic cell can reestablish the resting
potential and be ready to receive another signal
from the presynaptic cell.
 NEUROTRANSMITTER RECEPTORS
• Clearing of the neurotransmitter from the synaptic
cleft occurs in two ways:
Enzymatic degradation or
Reuptake (resorption back into the presynaptic
cells by specific transporter proteins).
THE ACETYLCHOLINE RECEPTOR
AND THE NEUROMUSCULAR
JUNCTION
• Synaptic transmission is mediated by the
neurotransmitter acetylcholine, which is released
into the synaptic cleft by the presynaptic neuron
• In the synaptic cleft, acetylcholine either binds to its
receptor on the postsynaptic cell or is rapidly
degraded by the enzyme acetylcholinesterase
• Upon binding , the muscle fiber is stimulated. There
is an influx of sodium ions into the postsynaptic
muscle fiber and the membrane becomes
depolarized, leading to an action potential, and
ultimately, muscle contraction
THE ACETYLCHOLINE RECEPTOR
AND THE NEUROMUSCULAR
JUNCTION
• The nerve gas sarin is a potent neurotoxin and
inhibitor of acetylcholineseterase, which affects an
accumulation of acetylcholine at the neuromuscular
junction.

• The high levels of acetylcholine in the synaptic cleft

lead to increased depolarization and contraction of
the muscle fibers;
however, without the ability to recover from
stimulation, the muscle fiber is inactivated, thus
leading to paralysis.
The GABA receptor and synapses
in the brain
• Brain neurons receive inputs from many cells, and
these signals can be contradictory.

• Some synapses can be excitatory, causing

depolarization similar to the neuromuscular junction,
and others can be inhibitory, reducing the chance of
depolarization

• The most prevalent neurotransmitter in the brain is

gamma-aminobutyric acid(GABA), which is a
derivative of the amino acid glutamic acid
The GABA receptor and synapses
in the brain
• GABA is released by the presynaptic neuron into
the synaptic cleft.
• It is bound by the GABA receptors on the
postsynaptic neuron or it is rapidly transported back
into the presynaptic cells.
• The GABA receptor is a ligand-gated ion channel,
which when open allows the flow of chloride ions
into the cells.
• The effect of the chloride ion influx is to make the
membrane potential even more negative and
counteract the effect of the sodium ion influx
associated with depolarization.
The GABA receptor and synapses
in the brain
• Therefore, GABA is considered an inhibitory
neurotransmitter that produces hyperpolarization in
the postsynaptic cell and reduces the likelihood of an
action potential in that neuron.
• Tranquilizers such as Valium enhance the normal
effects of GABA by binding to the GABA receptor and
increasing its ability to bind to GABA.
• The normal level of GABA results in a greater
inhibition of the postsynaptic neuron.
 CLINICAL CORRELATION
• NICOTINIC ACETYLCHOLINE RECEPTOR
CHANNELS:
Myasthenia gravis:
Is an autoimmune disease caused by antibodies
directed toward nAChR.

The disease results from a reduction in the num-

ber of functional nAChR by lysis of the postsynaptic
membrane following antibody binding,

which leads to destruction of the endplate region of

the muscle.
 CLINICAL CORRELATION
Myasthenia gravis:
It consists in muscle weakness that usually in-
creases with continued activity but improves after
periods of rest.
Any muscle can be affected, however, the muscles
that control eye movement, the eyelids, facial
expression and swallowing are most frequently
affected.
Congenital myasthenia:
• Disorders of the neuromuscular junction lead to
several types of myasthenia. Slow channel
congenital myasthenia
 CLINICAL CORRELATION
Congenital myasthenia:
Disorders of the neuromuscular junction lead to
several types of myasthenia.
Slow channel and
Fast channel syndrome

Slow channel
Inherited autosomal dominant syndrome, results
from mutations in the muscle nAChR channel
 CLINICAL CORRELATION
The increased duration of channel opening or
bursts of openings produce a prolonged excitatory
postsynaptic current, prolonged depolarisation of
the muscle membrane, inactivation of voltage-
gated Na+ channels and failure of muscle
excitability.
The prolonged de- polarisation also causes
enhanced Ca2+ entry, which may account for the
progressive destruction of the postsynaptic
neuromuscular junction.
CLINICAL CORRELATION
Fast channel syndrome:
Resembles symp- toms of slow channel syndrome,
but mutation in the nAChR channel produces a
reduction in ACh affinity and decreases the rate of
channel openings.

Fewer receptors are activated,

The excitatory postsynaptic current is reduced and

depolarisation is too small to elicit the action
potential.
 CLINICAL CORRELATION
• GLYCINE RECEPTORS CHANNEL:
Hyperekplexia:
Also called startle disease
is an autosomal dominant neurologic disorder
characterised by muscular rigidity of central nervous
system origin, particularly in the neonatal period,
and by an exaggerated startle response to
unexpected acoustic or tactile stimuli.
It results from mutations in the alpha1 sub- unit of
glycine receptor chloride channels that disrupt
inhibitory synaptic transition.
 CLINICAL CORRELATION
• VOLTAGE-GATED CALCIUM CHANNELS:
Lambert-Eaton myasthenic syndrome:
is an autoimmune disease, caused by antibodies to
calcium channels at the nerve terminal on which
acetylcholine release depends.
This results in a decrease in the amount of
acetylcholine released by the nerve impulse.
 CLINICAL CORRELATION
• VOLTAGE-GATED SODIUM CHANNELS:
• Mutations in the a subunit of voltage-gated sodium
channel (SCN4A) causes two types of autosomal
dominant skeletal muscle disorders:
Periodic paralysis and
Myotonia

PERIODIC PARALYSIS:
Characterised by attacks of muscle weakness or
paralysis between periods of normal muscle func-
tion.
Attacks usually begin early in life.
 CLINICAL CORRELATION
They tend to occur while resting after exercise and
last 1–2 h.
Weakness most commonly affects the muscles of
the arms and legs

MYOTONIA:
Myotonia is a general name for the clinical symptom
of delayed relaxation of skeletal muscle following
voluntary contraction.
The symptoms may worsen after repeated
exercise.
Weakness may occur.
 CLINICAL CORRELATION
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