MEMBRANE, ACTION POTENTIAL

&NEUROMUSCULAR TRANSMISSION
• Action Potential (AP) = electrical disturbance
propagated to the plasma membrane of
excitable cells (ex: nerve & striated cells)

• Resting membrane potential (RMP) : an

electrical state across the plasma membrane of
all cells , characterized by a (-) charge inside
relative to the outside. This is necessary for the
cell to fire an AP
RESTING MEMBRANE POTENTIAL

• RMP = -90 mV
• Na+ (outside): 142 mEq/L
• Na+ (inside): 14 mEq/L
• K+ (outside): 4 mEq/L
• K+ (inside): 140 mEq/L
  The flow of ions across the plasma membrane
down their electrochemical gradients is directly responsible for
generating much of the RMP

BASIC PHYSICS OF MEMBRANE POTENTIAL

• Membrane potentials are caused by diffusion of
ions across the plasma membrane
• K = highly concentrated inside , diffuses outside
creating electronegativity inside while
electropositivity outside the plasma membrane
• diffusion stops when diffusion potential is great
enough to block further net diffusion to the
exterior despite high K concentration inside
In mammalian nerve fiber K diffusion potential
is (-) 94 mV
• Na ions :
• highly concentrated outside ; low conc. inside
• diffusion to the inside creates a membrane
potential which is (+) inside and stops when
diffusion potential = (+) 61 mV is reached
 Nernst Potential = relation of diffusion to the
concentration difference
• the diffusion potential level across a membrane that exactly
opposes net diffusion of a particular ion through the
membrane.
• expressed as:
Nernst equation = +/- 61 x log conc. inside

conc. outside
• Importance of Nernst Equation:
1. Na, K & Cl are most important ions involved in the
development of membrane potentials in nerve, muscle as well
as neuronal cells in the nervous system
2. The degree of importance of each of the ions in determining the
voltage is proportional to the membrane permeability for that
particular ion.

3. A (+) ion concentration gradient from the inside

to the outside of the membrane causes
electronegativity inside the membrane
• Nondiffusible (-)anions inside are left behind
creating electronegativity inside plus Cl ions outside
diffuse to the inside following Na ions
4. Permeability of Na & K channels undergo rapid
changes during transmission of nerve impulse;
(Cl permeability does not change charges greatly)
Therefore rapid changes in Na & K permeability are
primarily responsible for signal transmission in neurons.

Na – K Pump:
• continually transports Na to the outside & K ions to the inside
of the cell
• an electrogenic pump because more (+) charges are pumped to the
outside than to the inside: 3Na  outside; 2K  inside
• Effects:
a. leaves a net deficit of (+) ions inside
b. causes (-) potential inside the cell
c. causes a large concentration gradient for Na & K across the
resting nerve membrane
d. indirectly contributes to the establishment of RMP
 Concentrations of Na & K during the resting
state:
• Na (outside) = 142 mEq/L
• Na (inside) = 14 mEq/L
• K (outside) = 4 mEq/L
• K (inside) = 140 mEq/L
• Leakage of K through the nerve membrane:
K channel : syn: “tandem pore channel” or K leak channel =
through which K can leak even in a resting cell
More permeable to K than Na = difference is a key factor in
determining the level of normal RMP
• ORIGIN OF THE NORMAL RM:
• Contributing factors:
1. K diffusion potential : ratio between K inside to K
outside = 35 : 1
2. Na diffusion thro’ the nerve fiber : ratio between Na
inside to Na outside = 0.1 with a calculated Nernst
potential for the inside of membrane = +61mV

The diffusion potentials alone caused by Na & K diffusion

would give a membrane potential of about (-) 86 mV;
almost all of this being determined by K diffusion.
Origin of the Normal
Resting Potential
• Contribution of the Potassium
Diffusion Potential
• Contribution of the Sodium Diffusion
through the Nerve Membrane
• Contribution of the Na+-K+ Pump
• The addition of (-) 4 mV is contributed to the membrane potential
by the continuously acting electrogenic Na-K pump giving a net
potential of (-} 90 mV
• Nerve Action Potential:
• rapid change in membrane potential that spreads rapidly along the
nerve fiber
• begins with sudden change from the (-) RMP
to a (+) potential & ends with an almost equally
rapid change back to (-) potential

In a nerve , the AP moves along the nerve fiber until it comes to the
fiber end.
• Stages of the Action Potential:
1. Resting stage:
• RMP before the action potential begins
• membrane is “polarized” during this stage
because of the (-) 90 mV membrane potential
2. Depolarized stage:
• membrane becomes very permeable to Na
• “polarized” state is lost. Potential rises rapidly in (+) direction
• In large nerve fibers membrane potential
“overshoots” beyond zero level (+) 35 mV
• In smaller nerve fibers & many CNS neurons this
approaches 0 level only
3. Repolarized stage:
• Na channels begin to close and Na influx stops
• K channels open so K effluxes and normal RMP
is reestablished

4. Hyperpolarized state: also known as (+) after potential

Occurs in :
- cardiac muscle for cardiac rhythm
- smooth muscle for peristalsis
- CNS neurons for rhythmical control of
breathing

Membrane becomes excessively permeable to K ions and becomes

more (-)

Re-excitation does not occur until K leak channels allow influx of K ions to
re-establish RMP level.
Voltage-Gated Sodium and Potassium Channels
 Voltage – Gated Na & K channels

• channels in addition to Na-K pump & K leak

channels
• Voltage – gated Na channel : necessary role in
causing both depolarization and repolarization
of the nerve during the AP
• Voltage – gated K channel : plays an important
role in increasing the rapidity of repolarization
of the membrane
Voltage – gated Na channels:

Features:

• has 2 gates:
• one near the outside of the channel
(activation gate)
• Another near the inside ( inactivation gate)
• During the normal resting membrane when
potential is (-) 90 mV , activation gate is closed
prevents any entry of Na ions to the interior of
the fiber through Na channels
 Activation of the Na channel:

• When the membrane becomes less (-) than

during the resting state , rising from (-) 90mV
toward 0, it finally reaches a voltage between (-)
70 – (-) 50 mV
• sudden conformational change in the activation
gate , flipping it all the way to the open position
• during this state, Na ions pour inward thro’ the
channel increasing permeability of the
membrane as much as 500 -5,000 fold
 Inactivation of the Na channels:

• The same increase in voltage that opens the

activation gate also closes the inactivation gate a
few 10,000ths of a sec after activation gate opens.
( Inactivation gate is slower than activation gate)
• Na ions no longer can pour to the inside of the
membrane & membrane potential begins to
recover back to normal toward the resting state =
Repolarization process which is needed before Na
channels open again.
Voltage – gated K channels:
resting state, gate is closed & K ions are prevented from
passing through the channel to the exterior

• Activation:
When membrane potential rises from (-) 90 mV towards
zero, a conformational opening of the gate allows
increased K diffusion outward through the channel
Open just at the same time that Na channels are
beginning to close.
Repolarization speeds up due to:
1. Decrease in Na entry
2. Simultaneous increase in K exit
 Initiation of the Action Potential
• Any event that causes enough initial rise in the
membrane potential from (-) 90 mv toward 0
• Operates by (+) feedback cycle, i.e., rising
voltage cause many voltage-gated Na channels
to begin opening.
• Effect : rapid inflow of Na ions to the interior
of the nerve fiber
 Threshold for initiation of the AP
• In a large myelinated nerve fiber : (-) 65 mv
followed by explosive development of an AP;

• Usually elicited with an adequate or threshold

stimulus applied on the nerve fiber.
 Propagation of the action potential

• Caused by more local circuits of current flow

farther along the membrane causing
progressively more & more depolarization until
it travels along the entire length of the fiber
• Direction of propagation:
• AP potential travels in all direction away from
the stimulus until entire membrane has
become depolarized
 Important role of energy metabolism
• Na & K concentration difference should be re-
established after repolarization ; achieved by Na-
K pump.:
• An active process; energy required to recharge
the nerve fiber and which is derived from the
active metabolic process from ATP (Na.K ATPase)
• Degree of activity is strongly stimulated when
excess Na ion accumulates inside the cell
membrane.
 Plateau in some APs
Occurs in: heart muscle fibers ; lasts for 0.2
-0.3 secs.
Causes contraction of the cardiac muscle with
the same duration.
 Causes of Plateau
1. voltage-gated fast Na channels : opening is
responsible for the Spike portion
2. voltage-activated Ca-Na channels or L-type Ca
channels: responsible for the Plateau portion: slow
to open and duration is prolonged allowing Ca ions
to enter the fiber
3. voltage-gated K channels : slow to open than usual;
delays the return of membrane potential towards
normal value
*Plateau ends when Ca-Na channels close & permeability
of K ions increases
 Roles of other ions during the AP:

1. Impermeant negatively charged ions(anions) inside

the nerve axon:
• cannot pass thro’ channels
e.g. : anions of protein molecules
• many organic phosphate compounds ,sulfate
compounds, etc.
• responsible for the (-) charge inside the fiber
when there is a net deficit of positively charged
K ions & other (+) ions.
2. Ca ions: serves along with Na or instead of Na
in some cells to cause most of the AP
• Voltage – gated Ca channels:
• slightly permeable to Na ions & Ca ions but
impermeability to Ca is greater than Na under
normal physiological conditions
• gating requires 10 -20 x as long for activation
compared to Na channels therefore called= slow
channels (Na channels= fast channels)
• opening of Ca channels = sustained depolarization;
whereas Na channels play a key role in initiating AP
 Ca channels are numerous in cardiac & smooth
muscle
• permeability of Na channels increase when there is
50% deficit in Ca level below normal
• Na channels are activated (opened) by a small
increase of the membrane potential from its normal
very (-) level
• Therefore, the peripheral nerve becomes highly
excitable sometimes discharging repetitively without
provocation called tetany ; sometimes lethal when
sustained muscle contraction involves the respiratory
muscles
 All – or- Nothing Principle: applies to all
excitable tissues
• Once an AP has been elicited at any point on
the nerve fiber membrane, depolarization
process travels over the entire membrane if
conditions are right, or it does not travel at all
if conditions are not right.
• Safety factor for propagation of AP = >1
• (ratio of AP to threshold for excitation must at
all times be greater than 1
SPECIAL FEATURES OF TRANSMISSION IN NERVE
TRUNKS
• Myelinated fibers: large fibers belong to type
1A α
• Axon is surrounded by myelin sheath which is
much thicker than axon itself
• Sphingomyelin, a lipid, an excellent insulator
contained in Schwann cells; decreases inflow
of impulses through the membrane by 5,000-
fold
 Node of Ranvier
• An insulated area about 2 – 3 micrometers in
length located between each 2 successive
Schwann cells
• Ions can still flow with ease through the axon
between the ECF & ICF.
• Important role: only site where Aps occur and
impulses are conveyed from node to node
called Saltatory conduction
 Value of Saltatory Conduction
• 1. Increases velocity of nerve transmission in
myelinated nerves as much as 5 – 50 fold
• 2. Conserves energy for the axon because only
the nodes depolarize therefore energy
requirement is minimal to re-establish Na & K
concentration difference across the membrane.
• 3. Decreases 50-fold the membrane capacitance
allowing repolarization to occur with little
transfer of ions.
Velocity of conduction in large myelinated
nerve fiber is 0.25 – 100 m/sec.
Excitation of the nerve fiber to elicit AP:
Through:
1.Mechanical disturbance of the membrane: this excites
sensory nerve endings in the skin
2.Chemical effects on membrane : chemical
neurotransmitters to transmit signals from neuron to
neuron
3.Electrical stimulation: electrical currents transmit signals
between muscle cells in heart and small intestines.
 Threshold of Excitation
Acute local potential : disturbance of local membrane potential for 1 msec. or more
after a mechanical stimulus is delivered

Acute subthreshold potentials: charges or local potentials that fail to elicit AP

Even a weak stimulus causes a local potential change at the membrane but intensity of
the local potential must rise to a threshold level before AP is set off.
 Absolute refractory period:
• Period during which a second AP cannot be
elicited even with a strong stimulus; lasts for
1/2500 seconds in large myelinated fibers.
• Happens when the membrane is still
depolarized from preceding AP.
• Reason: Na channels or Ca channels or both
become inactivated and no amount of
excitatory signal applied at this point will open
the inactivation gates.
 Inhibition of excitability
• 1. Stabilizers (membrane –stabilizing factor)
decreases excitability of the nerve fiber such as:
high ECF concentration of Ca decreases membrane
permeability to Na ions and simultaneously reduce
excitability.
2. Local anesthetics:
ex: procaine & tetracaine
act directly on activation gates of Na channels making
them much more difficult to open reducing membrane
permeability
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