Basic Concepts
Volt
A charge difference between two points in
space
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Basic Concepts
Ions – charged particles
Anions – Negatively charged particles
Cations – Positively charged particles
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Basic Concepts
Forces that determine ionic movement
Electrostatic forces
Opposite charges attract
Identical charges repel
Concentration forces
Diffusion – movement of ions through
semipermeable membrane
Osmosis – movement of water from region of
high concentration to low
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I. Membrane Potential
Separation of opposite charges across the membrane
leads to a constant potential difference across the
resting cell membrane
Cell’s ability to fire an action potential is due to the
cell’s ability to maintain the cellular resting potential
at approximately –70 mV (-.07 volt)
The basic signaling properties of neurons are
determined by changes in the resting potential
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Membrane Resting Potential
 Every cell has a separation of electrical charge across its
cell membrane.
 The membrane potential results from a separation of
positive and negative charges across the cell membrane.
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Membrane Resting
Potential
 excess of positive charges
outside and negative charges
inside the membrane
 maintained because the lipid
bilayer acts as a barrier to
the diffusion of ions
 gives rise to an electrical
potential difference, which
ranges from about 60 to 70
mV.
 (Microelectrode) 7
Concept of Resting Potential (RP)
 A potential difference across the cell
membrane at the resting stage or when
the cell is not stimulated.
 Property:
 It is constant or stable
 It is negative inside relative to the outside
 Resting potentials are different in different
cells.
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Resting Membrane Potential
Na+ and Cl- are more concentrated outside the
cell
K+ and organic anions (organic acids and
proteins) are more concentrated inside.
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Intracellular vs extracellular ion concentrations
Ion
Intracellular
Extracellular
Na+
K+
Mg2+
Ca2+
A-
5-15 mM
140 mM
0.5 mM
10-7 mM
65nM/L
145 mM
5 mM
1-2 mM
1-2 mM
0
Cl-
5-15 mM
110 mM
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Effect of The Sodium-Potassium Pump on
membrane potential(20%)
extrudes 3Na+
from the cell
while taking in
2K+
• Dissipation of ionic gradients is ultimately
prevented by Na+-K+ pumps
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Effect of movement of potassium alone on
Membrane Potential
 Potassium ions, concentrated inside the cell tend to
move outward down their concentration gradient through
non gated potassium channels/K+ leak channels
 But the relative excess of negative charge inside the
membrane tend to push potassium ions back in to the cell
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Potassium equilibrium
-90 mV
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Equilibrium Potentials
• The two major forces acting on ion movement are
the concentration and electrical gradients across the
membrane.
• When these forces are equal but acting in opposite
directions across a cell membrane for a particular ion
the membrane potential is also the equilibrium
potential for that ion.
Membrane potential that would exactly balance
the diffusion gradient and prevent the net
movement of a particular ion.
Calculating equilibrium potential
Nernst Equation
Allows theoretical membrane potential to be
calculated for particular ion.
Value depends on the ratio of [ion] on the 2
sides of the membrane.
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Nernst equation
Equilibrium potential (mV) , Eion =
ln RT
zF
[C]o
[C]i
where,
[C]o and [C]i = extra and intracellular [ion]
R = Universal gas constant (8.3 joules.K-1.mol-1)
T = Absolute temperature (°K)
F = Faraday constant (96,500 coulombs.mol-1)
z = Charge of ion (Na+ = +1, Ca2+ = +2, Cl- = -1)
For K+, with [K+]o = 4 mmol.l-1 and [K+]i = 150 mmol.l-1
At 37°C, EK = -97mV
ENa = +60mv
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Resting Membrane
Potential
Na+ is more concentrated
outside than inside and
therefore tends to flow into the
cell down its concentration
gradient
Na+ is driven into the cell
by the electrical potential
difference across the
membrane.
• Electrostatic and Chemical forces act together on
Na+ ions to drive them into the cell
• The Na+ channel close during the resting state
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Resting Membrane Potential
Resting membrane potential is less than Ek because
some Na+ can also enter the cell.
The slow rate of Na+ influx is accompanied by slow
rate of K+ outflux.
Depends upon 2 factors:
Ratio of the concentrations of each ion on the 2
sides of the plasma membrane.
Specific permeability of membrane to each
different ion.
Resting membrane potential of most cells ranges
from - 65 to – 85 mV.
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Factors that affect resting potential
 Difference of K+ ion concentration across the
membrane
 Due to the fact that the cell membrane at rest is
much more permeable to K+ ions than Na+ ions the
movement of K+ ions has a greater influence on
the resting membrane potential. The resting
membrane potential of the cell at rest in this case
is -70mV.
 Permeability of the membrane to Na+ and K+.
 Action of Na+ pump
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Basic Electrophysiological Terms I:
 Polarization: a state in which membrane is
polarized at rest, negative inside and positive
outside.
 Depolarization: the membrane potential
becomes less negative than the resting potential
(close to zero).
 Hyperpolarization: the membrane potential is
more negative than the resting level.
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Basic Electrophysiological Terms I:
 Reverspolarization: a reversal of membrane
potential polarity.
 The inside of a cell becomes positive relative to
the outside.
 Repolarization: restoration of normal
polarization state of membrane.
 a process in which the membrane potential
returns toward from depolarized level to the
normal resting membrane value.
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Objectives• To understand that rapid changes in permeability of
the neuronal membrane produce the action
potential.
• To recognize that altering voltage-gated ion
channels changes membrane permeability.
• To understand the movement of sodium and
potassium ions during the action potential.
• To examine refractory periods.
• To learn about conduction velocity.
Basic Electrophysiological Terms I:
 Polarization: a state in which membrane is
polarized at rest, negative inside and positive
outside.
 Depolarization: the membrane potential
becomes less negative than the resting
potential (close to zero).
 Hyperpolarization: the membrane potential is
more negative than the resting level.
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Basic Electrophysiological Terms I:
 Reverspolarization: a reversal of membrane
potential polarity.
 The inside of a cell becomes positive relative to
the outside.
 Repolarization: restoration of normal
polarization state of membrane.
 a process in which the membrane potential
returns toward from depolarized level to the
normal resting membrane value.
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The Action Potential
Neurons communicate over long distances by generating and
sending an electrical signal called a nerve impulse, or action
potential.
• The action potential is a large
change in membrane potential
from a resting value of about -70
millivolts to a peak of about +30
millivolts, and back to -70 millivolts
again.
• The action potential results from
a rapid change in the permeability
of the neuronal membrane to
sodium and potassium based on a
triggering event. The permeability
changes as voltage-gated ion
channels open and close.
The Action Potential Begins at the Axon
Hillock
• The action potential is generated at the axon
hillock, where the density of voltage-gated sodium
channels is greatest.
• The action potential begins when signals from the
dendrites and cell body reach the axon hillock and
cause the membrane potential there to become
more positive, a process called depolarization.
During Depolarization Sodium Moves
into the Neuron
• As the axon hillock depolarizes, voltagegated channels for sodium open rapidly,
increasing membrane permeability to
sodium.
• Sodium moves down its electrochemical
gradient into the cell.
voltage-gated sodium channels
Threshold
• If the stimulus to the axon hillock is great
enough, the neuron depolarizes by about 15
millivolts and reaches a trigger point called
threshold.
• At threshold, an action potential is
generated. Weak stimuli that do not reach
threshold do not produce an action potential.
Thus we say that the action potential is an all-
or-none event.
• Action potentials always have the same
amplitude and the same duration.
• At -55 millivolts the membrane is depolarized
to threshold, and an action potential is
generated.
• Threshold is a special membrane potential
where the process of depolarization becomes
regenerative, that is, where a positive
feedback loop is established.
An Action Potential is Generated When a Positive Feedback Loop
is Established
• When, and only when, a neuron reaches threshold, a positive feedback loop is
established.
• At threshold, depolarization opens more voltage-gated sodium channels.
• This causes more sodium to flow into the cell, which in turn causes the cell to
depolarize further and opens still more voltage-gated sodium channels.
• This positive feedback loop produces the rising phase of the action
potential.
rising phase
Inward flow
of Na
depolarization
Open
voltage-gated
Na channels
Interrupting the Positive Feedback Loop: VoltageGated Sodium Channels Inactivate
• The rising phase of the action potential ends when
the positive feedback loop is interrupted.
• Two processes break the loop:
1. the inactivation of the voltage-gated sodium
channels.
2. the opening of the voltage-gated potassium channels.
• The voltage-gated sodium channels have two gates:
1. A voltage-sensitive gate opens as the cell is
depolarized.
2. A second, time-sensitive inactivation gate stops the
movement of sodium through the channel after the
channel has been open for a certain time.
• At the resting membrane potential, the voltage
sensitive gate is closed.
• As the neuron is depolarized, the voltage-sensitive
gate opens.
• At a certain time after the channel opens, it
inactivates.
• At the peak of the action potential, voltage-gated
sodium channels begin to inactivate. As they inactivate,
the inward flow of sodium decreases, and the positive
feedback loop is interrupted.
voltage-sensitive
gate
time-sensitive
gate
resting
depolarized
inactive
Interrupting the Positive Feedback Loop:
Voltage-Gated Potassium Channels Open
• The voltage-gated potassium channels
respond slowly to depolarization. They
begin to open as the membrane
depolarizes, but responds so slowly that
they become fully activated only after the
action potential reaches its peak.
• potassium moves out of the cell as
voltage-gated potassium channels open. As
potassium moves out, depolarization ends,
and the positive feedback loop is broken.
• Both the inactivation of sodium channels
and the opening of potassium channels
interrupt the positive feedback loop. This
ends the rising phase of the action
potential.
Repolarization
•We have seen potassium leaving the cell as voltagegated potassium channels opened.
• With less sodium moving into the cell and more
potassium moving out, the membrane potential becomes
more negative, moving toward its resting value.
• This process is called repolarization.
Repolarization
Hyperpolarization
• In many neurons, the slow
voltage-gated potassium channels
remain open after the cell has
repolarized. Potassium continues
to move out of the cell, causing the
membrane potential to become
more negative than the resting
membrane potential.
• This process is called
hyperpolarization.
• By the end of the
hyperpolarization, all the
potassium channels are closed.
Hyperpolarization
• The rapid increase in sodium permeability is
responsible for the rising phase/Depolarization
of the action potential.
• The rapid decrease in sodium permeability
and simultaneous increase in potassium
permeability is responsible for the
repolarization of the cell.
• The slow decline in potassium permeability is
responsible for the hyperpolarization.
Ion Channel Activity During the Action Potential: Summary
•Rest.
•Voltage-gated sodium and potassium channels are closed when the neuron is at rest.
• Depolarization.
Voltage-gated sodium channels open rapidly, resulting in movement of sodium into the
cell. This causes depolarization.
• Repolarization.
Voltage-gated sodium channels continue to inactivate, then reset to the closed state.
Potassium channels continue to open. This results in a net movement of positive charge
out of the cell, repolarizing the cell.
• Hyperpolarization.
Some voltage-gated potassium channels remain open, resulting in movement of
potassium out of the cell. This hyperpolarizes the cell.
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The Relative Refractory Period
• Immediately after the absolute
refractory period, the cell can
generate another action potential,
but only if it is depolarized to a
value more positive than normal
threshold. This is true because
some sodium channels are still
inactive and some potassium
channels are still open. This is
called the relative refractory
period.
• The cell has to be depolarized to
a more positive membrane
potential than normal threshold to
open enough sodium channels to
begin the positive feedback loop.
The Action Potential is Propagated Along the Axon
• After an action potential is generated at the axon hillock, it is
propagated down the axon.
• Positive charge flows along the axon, depolarizing adjacent areas of
membrane, which reach threshold and generate an action potential.
The action potential thus moves along the axon as a wave of
depolarization traveling away from the cell body.
Conduction Velocity Depends on Diameter and Myelination of
the Axon
• Conduction velocity is the speed with which an action potential is propagated.
• Conduction velocity depends on two things:
1. The diameter of the axon.
• As the axon diameter increases, the internal resistance to the flow of
charge decreases and the action potential travels faster.
2. How well the axon is insulated with myelin.
• myelinated axons have areas of insulation interrupted by areas of bare
axon called nodes of Ranvier.
• In a myelinated axon, charge flows across the membrane only at the
nodes, so an action potential is generated only at the nodes. The action
potential appears to jump along the axon. This type of propagation is
called saltatory conduction.
• A myelinated axon typically conducts action potentials faster than an
unmyelinated axon of the same diameter.
• More speed is gained by insulating an axon with myelin than by increasing the
axon diameter.
λ = √R/Ri
Rm Membrane resistance
Ri Internal resistance
Table 4–1 Nerve Fiber Types in Mammalian Nerve.a
Fiber Type Function
Fiber
Conduc
Diameter tion
(m)
Velocity
(m/s)
A
alpha
Proprioception; somatic motor 12–20
70–120
beta
Touch, pressure
5–12
30–70
Gamma
Motor to muscle spindles
3–6
15–30
Delata
Pain, cold, touch
2–5
12–30
<3
3–15
0.4–1.2
0.5–2
0.3–1.3
0.7–2.3
B
Preganglionic autonomic
C
Dorsal root Pain, temperature, some
mechano-reception
SympatheticPostganglionic sympathetic
Nerve Fiber Types in Mammalian Nerve
For a television game show, 16 contestants volunteer to be stranded
on a deserted island in the middle of the South China Sea. They
must rely on their own survival instincts and skills. During one of the
challenges, one team wins a fishing spear. They catch a puffer fish
and cook it over the open flames of their barbecue. None of them
are very skilled in cooking, but they enjoy the fish anyway. One of
the contestants, a worldwide traveler, comments that it tastes like
Fugu. After dinner, they all develop a strange tingling around their
lips and tongue. They all become weak, and their frailty progresses
to paralysis. They all die. What was the cause of death?
A Tetrodotoxin
B Botulism
C Bacillus cereus food poisoning
D Tetanus
E Ciguatoxin
A well-meaning third year medical student accidentally
pushes an unknown quantity of KCl IV to a patient. If the
concentration of potassium outside a neuron were to
increase from 4 mEq/L to 8 mEq/L, what would you expect
to happen to the minimal stimulus required for initiation
of an action potential?
A The minimal stimulus required for initiation of an action potential would
remain the same
B The minimal stimulus required for initiation of an action potential would
increase
C The minimal stimulus required for initiation of an action potential would
decrease
D The minimal stimulus required for initiation of an action potential would stay
the same, but the amplitude of the peak of the action potential would increase
E The minimal stimulus required for initiation of an action potential would stay
the same, but the conduction velocity of the action potential down an axon would
slow
Clinical Focus
-Channelopathies
•Voltage-gated channels for sodium, potassium, calcium, and chloride are
intimately associated with excitability in neurons and muscle cells and in synaptic
transmission.
•Channelopathies affecting neurons include episodic and spinocerebellar ataxias,
some forms of epilepsy, and familial hemiplegic migraine.
•Ataxias are a disruption in gait mediated by abnormalities in the cerebellum and
spinal motor neurons. One specific ataxia associated with an abnormal potassium
channel is episodic ataxia with myokymia. In this disease, which is autosomaldominant, cerebellar neurons have abnormal excitability and motor neurons are
chronically hyperexcitable. This hyperexcitability causes indiscriminant firing of
motor neurons, observed as the twitching of small groups of muscle fibers, akin to
worms crawling under the skin (myokymia).
•One of the best-known sets of channelopathies is a group of channel mutations
that lead to the Long Q-T (LQT) syndrome in the heart. The QT interval on the
electrocardiogram is the time between the beginning of ventricular depolarization
and the end of ventricular repolarization. In patients with LQT, the QT interval is
abnormally long because of defective membrane repolarization, which can lead to
ventricular arrhythmia and sudden death
Local Anesthetics.
Among the most important stabilizers
are the many substances used clinically as local
anesthetics, including procaine and tetracaine. Most
of these act directly on the activation gates of the
sodium channels, making it much more difficult for
these gates to open, thereby reducing membrane
excitability.