DCM DPH 1.1 EXCITITATORY NEUR TX 24.pptx

RESTING MEMBRANE POTENTIAL
• This is the potential difference that exists across
the membrane of excitable cells, such as nerve and
muscle at rest).
• Membranes are polarized i.e. exhibit a resting
membrane potential.
• This means that there is an unequal distribution of
ions on the two sides of the nerve cell membrane.
1
MR NTONI GENERAL PHYSIOLOGY 2024

RESTING MEMBRANE POTENTIAL
• The resting membrane potential of large nerve fibres is -90mV.
• The potential inside the fibre is 90mV more negative than the
potential in the ECF on the outside of the fibre.
Note:
• The resting membrane potential of excitable cells falls in the
range of -70 to -90 mV.
• These values can best be explained by the concept of relative
permeabilities of the cell membrane.
• Thus, the RMP is close to the equilibrium potentials for K+ (-
85mV) and Cl- (-90mV) because the permeability to these ions at
rest is high.
• The resting membrane potential is far from the equilibrium
potentials for (+65) Na+ and (+120) Ca2+ because the permeability
to these ions at rest is low. 2

Factors that contribute to RMP
1. Na+-K+ pump
• Pumps 3 Na+ from the
inside to the outside
and 2 K+ from the
outside to the inside.
2. Proteins have a
negative charge &
can not leave the
cell to the outside.
3

Factors that contribute to RMP
3. Sodium and
Potassium
channels:
• Sodium channels are
closed.
• Some of the
potassium channels
are open(leaky).
4

ACTION POTENTIAL
• An action potential is a rapid change in membrane
potential that occurs when a nerve/muscle cell
membrane is stimulated.
• Action potentials are the basic mechanism for
transmission of information in the nervous system
and in all types of muscle.
5

Action Potential cont’d
• The membrane potential goes from the
resting potential (-90 mV) to some positive
value (about +35 mV) in a very short period
of time.
6

IONIC BASIS OF THE ACTION POTENTIAL
1. RMP. At rest:
• the membrane potential is approximately -70 mV (cell
interior negative).
• the K+ permeability is high, K+ channels are almost
fully open, allowing K+ ions to diffuse out of the cell
down the concentration gradient,
• this drives the membrane potential toward the K+
equilibrium potential (-85mV).
• the permeability to Cl- also is high.
• the Na+ conductance (permeability) is low hence the
RMP is far from the Na+ equilibrium potential
(+65mV).
7

2. Upstroke of the action potential:
• An adequate stimulation causes an inward current,
into a cell causing its depolarization to threshold at
approximately -55 mV.
• This initial depolarization causes rapid opening of
the activation gates of the Na+ channels, and the
Na+ conductance increases than the K+
conductance.
• The increase in Na+ conductance results in an
inward Na+ current which further depolarizes the
cell toward the Na+ equilibrium potential +65 mV .
• But only reaches about +35 mV.
MR NTONI GENERAL
YSIOLOGY 2024
8

3. Repolarization of the action potential.
At the peak of upstroke, the membrane potential
repolarizes back to the RMP as a result of two
events:
 The slow inactivation gates on the Na+ channels
finally respond to depolarization and closes but
slowly than opening of the activation gates.
 Depolarization opens K+ channels and increases K+
conductance to a value even higher than occurs at
rest.
Thus, an outward K+ current results, and the
membrane is repolarized.
MR NTONI GENERAL PHYSIOLOGY 2024 9

4. Hyperpolarizing.
• For a brief period after repolarization, the K+
conductance is higher than at rest, and the
membrane potential is driven closer to the K+
equilibrium potential (-85mV).
• Finally, the K+ conductance returns to the resting
level, and the membrane potential depolarizes
slightly, back to the resting membrane potential by
sodium-potassium pump.
• The membrane is now ready, if re-stimulated, to
generate another action potential.

SUMMARY.
• At rest, the activation gate is closed, although the
inactivation gate is open, Na+ cannot move through
the channel.
• Suprathreshold depolarization causes the activation
gates to open quickly. The inactivation gates are still
open, thus, both gates are open briefly leading to an
influx of Na+ ions into the cell, causing further
depolarization (the upstroke).
• At the peak of the action potential, the slow
inactivation gates finally respond to depolarization
and closes the channel thus repolarization begins
leading to closure of the activation gate as well as
opening the inactivation gates (original positions).

Action potential cont’d

13

• The successive stages of the action potential
are as follows
1. Resting stage
2. Depolarisation
3. Repolarisation
4. Hyperpolarisation
14

Resting Stage
• This is the resting membrane potential before the
action potential begins.
• The membrane is said to be “polarized” during this
stage because of the –90 mV negative membrane
potential that is present.
• At rest, the activation gate is closed. Although the
inactivation gate is open, Na+ cannot move
through the channel.
15

16

17

Depolarisation
• When a nerve is adequately stimulated, Na+ - channels are
triggered to open allowing Na+ ions to diffuse rapidly into
the cell reducing the negative RMP to a less value.
• When the local depolarisation surpasses a limit called the
threshold potential (-55mV ).
• During the upstroke of the action potential, depolarization
to threshold causes the activation gate to open quickly. The
inactivation gate is still open because it responds to
depolarization more slowly than the activation gate.
• Thus, both gates are open briefly, and Na+ can flow through
the channel into the cell, causing further depolarization (the
upstroke).
• This shifts the membrane potential towards 0mV. 18

Repolarization
• At the peak of the action potential (+35mV), the
slow inactivation gate finally responds and closes,
and the channel itself is closed.
• Repolarization begins.
• When the membrane potential has repolarized
back to its resting level, the activation gate will be
closed and the inactivation gate will be open, both
in their original positions.
19

Repolarization cont’d
• Again, once the peak of the neuron’s AP is reached
(+35mV) the MP begins to move back towards the
RMP (-90mV) in a process called repolarization
• The rise of the MP from -90mV towards 0mV also
opens the voltage sensitive K+ ion channels
• However they just open at the same time the
sodium channels are beginning to close
• The decrease in Na entry and simultaneous
increase in K+ exit from the cell, combine to speed
up the repolarization process that leads to full
recovery of RMP
20

Repolarization cont’d
• The K+ channels open more than they normally do
during repolarization and their return to the closed
state is slow
• Thus too many K+ ions may rush out of the cell,
this causes a brief period of hyperpolarisation
before the RMP is restored by the action of Na – K
pump
21

All or non law
• Application of a threshold stimulus either
produces a full response or not at all.
• Further increase in the intensity of a stimulus
produces no increment or other changes in
action potential.
• The action potential fails to occur if the
stimulus is sub-threshold, it produces only
local changes with no propagation
22

• During the upstroke of an action potential:
 Na permeability increases
 due to opening of Na+ channels
Na+ channels
 K permeability increases
due to opening of K+ channels
Membrane
hyperpolarized
resting potential
K+ channels
• During the down stroke of an action
potential:
 Na permeability decreases
 due to inactivation of Na+ channels
1 ms
+61
0
(mV)
-90
ENa
EK
23

Na+ channels
• After hyperpolarization of
membrane following an action
potential:
Membrane
hyperpolarized
resting potential
K+ channels
not always seen!
There is increased K+
conductance
due to delayed closure of
K+ channels
1 ms
+61
0
(mV)
-90
ENa
EK
24

Plateau in Some Action Potentials
25

Action Potentials cont’d
• The usual voltage-activated sodium channels
(fast channels)
• Voltage-activated calcium-sodium channels
which are slow to open (slow channels)
• Opening of fast channels causes the spike
portion of the action potential
26

Action Potentials cont’d
• The slow calcium-sodium channels allows
calcium ions to enter the fiber, which is
largely responsible for the plateau portion of
the action potential
• The voltage-gated potassium channels are
slower than usual to open, often not opening
very much until the end of the plateau
27

Absolute Refractory periods
• During an action potential, a second stimulus
will not produce a second action potential
• Corresponds to the period when the voltage
gated sodium channels are still open
28

Relative refractory periods
• Another action potential can be produced,
but only if the stimulus is greater than the
threshold stimulus.
• Corresponds to the period when the
potassium channels are open
29

Impulse conduction
• An impulse is simply the movement of action
potentials along a nerve cell.
• In unmyelinated axons, voltage-gated sodium
and potassium channels are distributed
uniformly along the length of the axonal
membrane.
30

Propagation of an impulse cont’d
• An action potential is
generated when the
axon hillock is
depolarized by the
passive spread of
synaptic potentials
along the somatic and
dendritic membrane
31

• The entry of sodium ions into the axon hillock
causes the adjacent region of the axon to
depolarize as the ions that entered the cell,
during the peak of the action potential, flow
away from the sink.
32

• This local spread of the current depolarizes
the adjacent region to threshold and causes
an action potential in that region.
• By sequentially depolarizing adjacent
segments of the axon, the action potential
moves along the length of the axon
33

34

SALTATORY CONDUCTION
• In myelinated axons all voltage gated sodium
channels are concentrated between the
nodes of Ranvier
35

Saltatory conduction cont’d
• When an AP is initiated at the axon hillock, the
influx of Na+ causes the adjacent node of ranvier
to depolarize
• This, in turn, causes depolarization of the next
node of Ranvier and the eventual initiation of an
action potential
36

Saltatory conduction cont’d
• Action potentials are successively generated
at neighbouring nodes of ranvier.
• Therefore, the action potential in a
myelinated axon appears to jump from one
node to the next.
37

Saltatory Conduction: Action Potential Propagation
in a Myelinated Axon
38

SYNAPSE
• Is a site where information is transmitted
from one cell to cell.
• The information can be transmitted either
electrically (electrical synapse) or via
chemical transmitter (chemical synapse)
• So, there are two major types of synapses:
1. Chemical synapse
2. Electrical synapse
39

ELECTRICAL SYNAPSE
• Electrical synapses allow current to flow from
one excitable cell to the next via low resistance
pathways between cells called gap junctions.
• Gap junctions are sites for very fast conduction
in these tissues.
Examples
• Gap junctions in smooth muscle and cardiac
muscle cell ﬁbers.
40

CHEMICAL SYNAPSES
• In chemical synapses, there is a gap between the
presynaptic c.m and postsynaptic c.m (synaptic cleft).
• Information is transmitted across the synaptic cleft via
neurotransmitter substance released from the presynaptic
terminal and binds to receptors on postsynaptic terminal.
• Contains 3 parts
1. Axon Terminal- filled with vesicles containing
neurotransmitter
2. Synaptic Cleft- space between the neurons
3. Neurotransmitter Receptor Region- located on the post
synaptic neuron
41

SYNAPTIC INPUT-EXCITATORY AND INHIBITORY
POSTSYNAPTIC POTENTIALS
1. Excitatory Postsynaptic Potentials (EPSPs).
• EPSPs are synaptic inputs that depolarize the postsynaptic
cell, making its membrane potential closer to threshold and
closer to firing an action potential.
• EPSPs are produced by opening Na+ and K+ channels, similar
to the nicotinic ACh receptor.
• The membrane potential is driven to a value approximately
halfway between the equilibrium potentials for Na+ and K+,
or 0 mV, which is a depolarized state.
• Excitatory neurotransmitters include ACh, norepinephrine,
epinephrine, dopamine, glutamate, and serotonin.
42

2. Inhibitory Postsynaptic Potentials (IPSPs).
• Inhibitory postsynaptic potentials (IPSPs) are
synaptic inputs that hyperpolarize the postsynaptic
cell, making its membrane potential away from
threshold and farther from firing an action
potential.
• IPSPs are produced by opening Cl- channels.
• The membrane potential is driven toward the Cl-
equilibrium potential (approximately -90 mV),
which is a hyperpolarized state.
• Inhibitory neurotransmitters are γ-aminobutyric
acid (GABA) and glycine. 43

AP transfer across a synapse
• When an action potential depolarizes the
presynaptic membrane
• Calcium channels open and allow large numbers
of calcium ions to ﬂow into the terminal.
• The calcium ions stimulate vesicles to release
their neurotransmitter into the cleft by
exocytosis.
• The neurotransmitter molecules diffuse across
the cleft and fit into receptor sites in the
postsynaptic membrane.
44

AP transfer across a synapse cont’d
• If the neuro – transmitter is excitatory e.g
acetylcholine and noradrenaline.
• It causes slight depolarization of the
postsynaptic cell by the opening of sodium
channels in the postsynaptic membrane and
the influx of sodium ions from ECF.
• This slight depolarization is called excitatory
postsynaptic potential (EPSP) as earlier
mentioned.
45

• EPSP in turn causes development of action
potential in the initial segment of the axon of
the postsynaptic neuron.
• If the neuro – transmitter is inhibitory e.g.
gamma aminobutyric acid (GABA) and
dopamine.
• It causes opening of potassium channels in the
postsynaptic membrane and efflux of potassium
ions----postsynaptic cell becomes
hyperpolarised
46

• This hyperpolarization is also referred to as
the inhibitory postsynaptic potential (IPSP).
• When IPSP is developed, the action potential
is not generated in the postsynaptic neuron.
47

Sequence of Events at the Neuromuscular
Junction
48

Sequence of events in neuromuscular transmission.
1. Action potential travels down the motoneuron to the
presynaptic terminal.
2. Depolarization of the presynaptic terminal opens Ca2+
channels, and Ca2+ flows into the terminal.
3. Acetylcholine (ACh) is extruded into the synapse by
exocytosis.
4. ACh binds to its receptor on the motor end plate.
5.Channels for Na+ and K+ are opened in the motor end plate.
6.Depolarization of the motor end plate causes action
potentials to be generated in the adjacent muscle tissue.
7.ACh is degraded to choline and acetate by
acetylcholinesterase (AChE); choline is taken back into the
presynaptic terminal on an Na+-choline cotransporter.
49

Integration of Synapic
information:
50

The presynaptic information arriving at the synapse may
be integrated in one of two ways:
1. Spatial Summation
• Spatial summation occurs when two or more presynaptic
inputs arrive at a wide space of the postsynaptic cell
membrane simultaneously.
• Excitation of a single presynaptic terminal on the surface of a
neuron almost never excites the neuron.
• If both inputs are excitatory, they will combine to produce
greater depolarization than either input would produce
separately.
• If one input is excitatory and the other is inhibitory, they
will cancel each other out.
• Spatial summation may occur, even if the inputs are far
apart on the nerve cell body, because EPSPs and IPSPs are
conducted so rapidly over the cell membrane. 51

52

2. Temporal Summation
• Here, successive discharges from a single
presynaptic terminal, occur rapidly enough, can add
to one another; that is, they can “summate.”
• Temporal summation occurs when two presynaptic
inputs arrive at the postsynaptic cell in rapid
succession.
• Because the inputs overlap in time, they summate.
• Successive discharges from a single presynaptic
terminal, if they occur rapidly enough, can add to one
another and increase the postsynaptic potential to a
greater level
53

54

Fatigue of Synaptic Transmission
• When an excitatory synapse is stimulated
rapidly
• The number of discharges by the
postsynaptic neuron is at first great, but
becomes less in succeeding milliseconds
• Due to partial depletion of the stores of
transmitter substance
55

Synaptic Delay
• The synaptic delay is the time required for the
multiple steps in chemical neurotransmission to
occur.
• OR Time consumed during transmission of a
neuronal signal from a presynaptic neuron to a
postsynaptic neuron
1. Discharge of the transmitter substance by the
presynaptic terminal
2. Diffusion of the transmitter to the postsynaptic
neuronal membrane
56

Synaptic Delay cont’d
3. Action of the transmitter on the membrane
receptor.
4. Action of the receptor to increase the
membrane permeability.
5. Inward diffusion of sodium to raise the
excitatory postsynaptic potential to a high
enough level to elicit an action potential.
57

Muscular system.

Muscular system…
• There are three types:
1. Skeletal:
 Attached to bones
 Striated
 Under voluntary control
 Multinucleated muscle fibers
2. Smooth:
Located in walls of hollow tissues
Non striated
Under involuntary control
Uni-nucleated muscle fibers 59

• 3. Cardiac:
Forms most heart tissue.
Is striated
Is under involuntary control
Is autorhythmic
Uni-nucleated or binucleated
Review of Histology:
1. Skeletal muscle
• A muscle consists of a large number of muscle fibres/
muscle cells.
• The entire muscle is covered in a connective tissue
sheath called the epimysium.

 Within the muscle, the cells
are collected into separate
bundles called fascicles, and
each fascicle is covered in
its own connective tissue
sheath called the
perimysium.
 Within the fascicles are
the individual muscle
cells, each wrapped in a
fine connective tissue
layer called the
endomysium.

(a)Sarcolemma: This is the muscle fiber (cell)
membrane.
(b)Sarcoplasm:
• Is a muscle fiber cytoplasm.
• Contains glycogen granules (glycosomes).
• Contains oxygen binding protein (myoglobin).
• Almost completely filled with contractile filaments
called myofilaments.
(c) Sarcoplasmic reticulum:
• Is the SER of the muscle fiber.
• Is a net work of tubes surrounding myofibrils.
• Reabsorbs calcium ions during relaxation.
• Releases calcium ions during contraction.

(d) Transverse tubules:
• Are tubules formed by invaginations of the sarcolemma and
flanked by SR.
• They carry action potential deep into the muscle fibers.
• T. tubules and SR provide tightly linked signals for muscle
contraction.
• There T. tubules at each A-band/I-band junction and they
are continuous with the sarcolemma.
• They conduct electrical impulses throughout the cell (every
sarcomere); the electrical impulse signals for the release of
calcium ions from the adjacent terminal cisternae.
• T. tubule proteins (dihydropyridine) acts as voltage sensors.
• SR foot proteins (ryanodine) receptors regulate calcium
release from S.R cisternae.

(e) Myofibrils:
• Is a bundle of thread like contractile elements
consisting of myofilaments.
• They make up 80% of the muscle volume
• They contain the contractile elements of the
skeletal muscle.

(f) Myofilaments:
• Are extremely thread like proteins
• They are of three types:
(i) Thick filaments (16nm) called myosin.
 During muscle contraction, myosin heads link the
thick and thin filaments together forming cross
bridges.
 Each myosin molecule has a road like tail and two
globular heads.

Thick filaments

(ii) Thin filaments (8nm) called actin:
 Actin provides active sites where myosin heads
attach during contraction.
 Tropomyosin and troponin are regulatory subunits
bound to actin.
 Troponin T for tropomyosin attaches the
troponin complex to tropomyosin.
 Troponin I for inhibition of actin and myosin by
covering the myosin-binding site on actin.
 Troponin C is a Ca2+-binding protein that plays a
central role in the initiation of contraction.
(iii) Elastic filaments (read their role).

Thin filaments…

(g) Sarcomere:
• Is the smallest contractile unit of a muscle fiber.
• Its characterized by alternating light and dark
bands or zones produced by myofilaments:
 Z-discs: Lines that separate individual sarcomeres.
 M-line: Central line of sarcomere where myosin
filaments are anchored.
 H-zone: Area where only myosin filaments are
present.
 I- zone: Is where only actin filaments are present.
 A-band: Includes overlapping myosin and actin
filaments MR NTONI GENERAL PHYSIOLOGY 2024 72

(g) Sarcomere…

For contraction to occur:
The skeletal muscle must:
• Be adequately stimulated by a motornerve ending.
• Propagate an electrical current/action potential
along its sarcolemma.
• Have arise in intracellular calcium levels, the final
stimulus for contraction as shown below.

Skeletal muscle contraction (sliding filament model)
• Excitation-contraction coupling in skeletal
muscle is the sequence of events linking
transmission of an action potential along a
sarcolemma to muscle contraction (the sliding of
myofilaments).
• The sarcolemma like other plasma membranes is
polarized at rest.
• Also ATP attached to myosin head is split by ATPase
causing myosin heads to be active.

EXCITATION-CONTRACTION COUPLING IN SKELETAL
MUSCLE
Temporal sequence of events in
excitation-contraction coupling in
skeletal muscle.
The muscle action potential precedes a
rise in intracellular [Ca2+], which
precedes contraction.
77

Steps to Excitation-contraction coupling and muscle
contraction
• AP (impulse) is propagated along the axon of a
motorneuron.
• Depolarization of the presynaptic membrane (Na ions
influx).
• Fusion of synaptic vesicles with presynaptic
membrane.
• Exocytosis of Ach into the synaptic cleft.
• Diffusion of Ach into the synaptic cleft.
• Binding of Ach to receptors in postsynaptic
membrane.
• Depolarization of the postsynaptic membrane and the
surrounding sarcolemma (Na ions influx).

• Depolarization of T-tubules (sarcolemmal
invaginations).
• Depolarization of cisternae of S.R and the whole
S.R.
• Release of stored calcium ions from S.R into
sarcoplasm surrounding myofibrils.
• Binding of calcium ions to troponin Cs of the
troponin complexes.
• Troponin then pulls the tropomyosin, changing its
position so the binding sites are exposed.
79

• Myosin heads bind to actin filaments to form a
cross bridge, ATP drives myosin heads generating a
power stroke pulling the actin filaments of the
sarcomere to the center.
• Pi and ADP falls off to create room for new ATP
molecule onto myosin head.
• Since thin filaments are anchored in Z-line, their
sliding causes the sarcomere to shorten.
• Sarcomeres shorten (I bands shorten, A bands
don’t) and consequently the whole muscle
shorten.
80

POWER STROKE..

Steps in muscle relaxation
• After a few milliseconds of the action potential.
• The calcium pump transports Ca2+ ions present in the
sarcoplasm during contraction, back into the
longitudinal portion of the sarcoplasmic reticulum,
from where the Ca2+ ions are restored.
• Removal of calcium from troponin restores blocking
action of the troponin–tropomyosin complex.
• Myosin cross-bridge cycle closes and muscle relaxes.
83

Smooth muscle:
• Exists in most hollow organs.
• Not striated.
• Not arranged in sarcomeres.
• Controlled involuntarily.
• Filaments don’t form myofibrils.
• Vital for peristalsis.

Contraction:
 Cells usually arranged in sheets with in muscles.
 Their cells are organized in in two layers
(longitudinal and circular) of closely opposed fibers
 Have essentially same contractile mechanisms as
skeletal muscles.
 Their cells have three types of filaments:
• Thick myosin filaments longer than for skeletal
muscles
• Thin actin filaments with tropomyosin but devoid of
troponin
• Filaments of intermediate size for cell
support/cytoskeleton.

 They contain dense bodies containing same
proteins found in Z-lines.
 Their whole sheets exhibit slow, synchronized
contractions.
 Action potentials are transmitted from cell to cell
 Some lack neuromuscular junctions
 Some of their cells act as pacemakers and set
contractile pace for a whole sheet of muscle.
 Some of their cells are self excitatory and
depolarize without external stimuli.

Stimuli for smooth muscle contraction:
Spontaneous electrical activity in plasma
membrane of muscle fiber
Neurotransmitter released by autonomic
neurons.
Hormones
Local inducers like osmolarity, ion concentration,
acidity of ECF
Stretch.

Contraction:
• Muscle fiber is stimulated.
• Calcium released into the cytoplasm from ECF.
• Calcium ions bind to calmodulin.
• Calcium calmodulin activates myosin light chain
kinase
• Myosin light chain kinase phosphorylates the
light chains in myosin heads and increases their
ATPase activity.
• Active myosin can now cross bridge with actin
and create muscle tension.

DCM DPH 1.1 EXCITITATORY NEUR TX 24.pptx

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