Розробник: к.мед.н., доцент І.М.

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Затверджено на засіданні кафедри № 24
від 28.08.2019

INTRODUCTION TO PHYSIOLOGY.
EXCITABLE TISSUES.
MEMBRANE POTENTIALS

Lecture 1
 LECTURE OUTLINE
1. Main terms of physiology. Principles of
physiological functions. Homeostasis and its
regulation.
2. Irritability. Types of irritants.

3. Excitable tissues and their properties.

4. Membrane-ionic theory. Rest Membrane Potential

origin.
5. Process of excitation. Action Potential.

6. Changes of excitability during excitation

 Physiology
is the foundation of medical practice
The word physiology is from the Ancient
Greek φυσιολογία (phusiología, "natural
philosophy") and it is the study of how
organisms perform their vital functions
Physiology is the science which studies biological
functions (mechanisms of vital activity) of whole
healthy organism and regulation of these
functions during its adaptation to changes of
ambient conditions.

In other words,
physiology is the science about the
dynamics of vital functions
 MAIN TERMS OF PHYSIOLOGY
Physiological system is the inherited totality of
organs and tissues that perform the same
function (or sometimes several
functions).

Function (from Greek functio – activity)

is a specific activity of specialized
structures (at different levels: from
single-cell up to the population) which is
directed to the achievement of final
positive adaptive result.
Continuous adaptation and therefore final positive adaptive
result are possible because of regulation process.
Regulation – is the complex of processes which ensure
the adjustment of organs and systems functional
activity to different environmental conditions.
Mechanism – is the way (manner) to regulate function
(local or central, nervous or humoral, etc.)
Self-regulation – is the complex of processes to return
the functional activity of organs to the initial (normal)
level.
Factor which initiates self-regulation is any fluctuation
of function which is out from the normal range.
Homeostasis is relative constancy of internal
environment and stability of main physiological
functions which are provided by totality of
physiological regulatory mechanisms.
Functional Systems are the fundamentals of self-regulation
are the dynamic unity of central and peripheral structures and
mechanisms; their coordination supplies achievement of final positive
adaptive results.

FUNCTIONAL SYSTEM

Anatomical Auxiliary Regulative

apparatus apparatus apparatus
Structure elements Fulfilment of function Elements which ensure
intended for fulfilment is impossible without all mechanisms of
of function these elements regulation

USEFUL ADAPTIVE
RESULT
 Regulatory mechanisms

neural humoral

Reflex

Reflex arc

6 components
 Principle scheme of reflex arch
3 links = 6 components

1. Receptive
2.Afferent neuron
field

6. FEED-BACK
3.NERVE
Adaptation CENTER
COMMUNICATION
to stimulus

5.Organ-effector 4.Efferent neuron

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 Organ-effector

Muscles: glands neurons

Skeletal
Smooth
cardiac

EXCITABLE TISSUES
Excitable tissues and their properties.
Types of irritants
Every living tissue can exist in two states:
rest and activity

Rest state → stimulus → active state

The irritant (stimulus) of living cell or even the whole organism is
any change of internal or external environment,
which can be perceived by cells and can cause the response reaction

To cause the response reaction the irritant must meet some

requirements:

1) It must have the threshold strength – the minimal strength which is able to
cause response reaction.
2) Threshold irritant must act during definite time which is enough to cause the
response reaction – utilization time.
3) Irritant must have differential transconductance (steepness). If the strength of
irritant increases from subthreshold to threshold too slowly, the cell “has time”
for adaptation to this stimulus, so the cell will not respond to such stimulus.

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 Classification of irritants
According to the strength of irritant

threshold suprathreshold subthreshold

strength
Minimal strength of irritant
which is able to which is able to strength of irritant
cause response cause response which is unable to
reaction. reaction (stronger cause response
than threshold). reaction (lesser than
threshold) .

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 Classification of irritants
According to the nature of irritant

Physical Physical-chemical Chemical

chemical
- temperature; - osmotic compounds
- mechanical; pressure; 1) produced in
- electrical; - pH; organism –
- light; - electrolyte hormones,
- sound composition; metabolites;
- colloid state 2) entering from
outside – acids,
alkalis, drugs,
poisons
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3. Excitable tissues and their properties

14
 Manifestation of excitability is a state of excitation.
Excitation is the specific state of excitable tissue which
is characterized by rapid changes of cell membrane
voltage and leads to the specific response.

Nerve Fiber Muscular Fiber Secretory Cell

EXCITATION =
Action Potential

Nerve Muscle Glandular

Impulse Contraction Secretion

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 Physiological properties of excitable tissues:
• 1. Excitability is a property of excitable tissues to generate
action potential in response to internal or external
adequate stimulus
• 2. Conductivity is a property of excitable tissues to conduct
action potential (nerve impulse)
• Specific for nerve fibers
• 3. Contractility is a property of excitable tissues to change
the length and (or) tension (contraction)
• Specific for muscles
• 4. Automaticity is a property of excitable tissues to generate
action potential automatically (by themselves)
• Specific for cardiac muscles
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 4. Membrane-ionic theory
Rest Membrane Potential (RMP) origin

• 1896 - Chagovets advanced the idea of the ionic

nature of the bioelectrical processes and tried to
explain them by means of Arrhenius' theory of
electrolytic dissociation.
• 1902 - Bernstein developed the membrane-ionic
theory.
• 1949-1952 – the membrane-ionic theory was modified
and substantiated experimentally by Hodgkin, Huxley
and Katz.

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REST STATE = RESTING MEMBRANE POTENTIAL
• The resting membrane potential (RMP, RP) is the
potential difference that exists across the membrane
of excitable cells such as nerve and muscle in the
period between action potentials (i.e., at rest).
• The resting membrane potential is established by
diffusion potentials, which result from the
concentration differences for various ions across the
cell membrane.
• These concentration differences have been
established by primary and secondary active
transport mechanisms.
 CHARACTERISTICS OF
CELL MEMBRANES

 Cell membranes are composed primarily of lipids

and proteins.
 The lipid component consists of phospholipids,
cholesterol, and glycolipids and is responsible for
the high permeability of cell membranes to lipid-
soluble substances such as carbon dioxide,
oxygen, fatty acids, and steroid hormones and
also responsible for the low permeability of cell
membranes to water-soluble substances such as
ions, glucose, and amino acids.
 The protein component of the membrane consists
of transporters, enzymes, hormone receptors,
cell-surface antigens, and ion and water channels.
 Proteins in cell membranes may be either
integral or peripheral

• Integral membrane proteins • Peripheral membrane proteins are

• Some integral proteins are loosely attached to either the
transmembrane proteins; thus, they intracellular or extracellular side of
are in contact with both ECF and ICF. the cell membrane by electrostatic
interactions
• Examples of transmembrane
integral proteins are: • One example of a peripheral
membrane protein is ankyrin, which
• ligand-binding receptors (for “anchors” the cytoskeleton of red
hormones or neurotransmitters), blood cells to an integral membrane
• transport proteins (Na+-K+ ATPase), transport protein, the Cl−-HCO3−
• pores, exchanger
• ion channels,
• cell adhesion molecules,
• G proteins.
 TRANSPORT ACROSS
CELL MEMBRANES
• Substances may be transported down an electrochemical
gradient (downhill) or against an electrochemical gradient
(uphill).
• Downhill transport occurs by diffusion, either simple or
facilitated, and requires no input of metabolic energy.
• Uphill transport occurs by active transport, which may be
primary or secondary.
• Primary and secondary active transport processes are
distinguished by their energy source.
• Primary active transport requires a direct input of metabolic
energy;
• Secondary active transport utilizes an indirect input of
metabolic energy.
Summary of Membrane Transport
 Facilitated diffusion, primary and secondary active
transports are protein-mediated transport which is
characterized by following:

• 1. Stereospecificity is transportation of only definite

molecules;
• 2. Saturation phenomenon (saturation of
transporters, for example renal threshold for
glucose);
• 3. Concept of competition (for similar molecules, for
example, glucose – galactose)

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 Ion Channels

• Ion channels are integral, membrane-spanning proteins that,

when open, permit the passage of certain ions.
Types of ionic channels:
1. Unregulated channels (ungated (Leak))
• Always open
• Direction the ion moves depends upon electrochemical forces
• Important for determining resting membrane potential of a
cell
2. Regulated channels (gated channels): can be opened or
closed by gates.
 Regulated channels

♦ Voltage-gated channels have gates that are controlled by changes

in membrane potential.
♦ Second messenger-gated channels have gates that are controlled
by changes in levels of intracellular signaling molecules such as
cyclic adenosine monophosphate (cyclic AMP) or inositol 1,4, 5-
triphosphate (IP3).
The sensors for these gates are on the intracellular side of the ion
channel.
♦ Ligand-gated channels have gates that are controlled by
hormones and neurotransmitters.
The sensors for these gates are located on the extracellular side of
the ion channel.
States of regulated channels

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 Diffusion Potential
• is the potential difference
generated across a membrane
when an ion diffuses down its
concentration gradient
• (caused by diffusion of ions)
• diffusion potential can be
generated only if the
membrane is permeable to
that ion.
Equilibrium Potentials
• If there is the diffusion
potential is created eventually,
net diffusion of the ion slows
and then stops
• The equilibrium potential is
the diffusion potential that
exactly balances or opposes
the tendency for diffusion
down the concentration
difference.
Generation of an Na+ diffusion potential.
 Nernst Equation

• The Nernst equation is used to calculate the equilibrium potential for an ion at
a given concentration difference across a membrane, assuming that the
membrane is permeable to that ion. The equilibrium potential is calculated for
one ion at a time.
1. The ion always diffuses in a direction that brings the Em toward
its equilibrium.
2. The conductance of the ion is directly proportional to the net
force and the permeability (determined by ion channel state) of
the membrane for the ion.
3. The Em moves toward the EX of the most permeable ion.
4. Equilibrium potential for ions are vary
• The resting membrane potential (RMP) of excitable
cells falls in the range of −70 to −90 mV.
• RMP is close to the equilibrium potentials for K+ and
Cl− because the permeability to these ions at rest is
high.
• RMP is far from the equilibrium potentials for Na+
and Ca2 + because the permeability to these ions at
rest is low.
 The Goldman-Hodgkin-Katz equation
• allows to calculate membrane potential on the inside of the
membrane when two univalent positive ions, sodium (Na+)
and potassium (K+), and one univalent negative ion, chlorine
(Cl–), are involved.

𝑷𝑲+ ∙𝑲𝒊𝒏 +𝑷𝑵𝒂+ ∙𝑵𝒂𝒊𝒏 +𝑷𝑪𝒍− ∙𝑪𝒍𝒊𝒏

𝑬𝑴𝑭𝑴 = ±𝟔𝟏 ∙ 𝒍𝒈 = –90 mV
𝑷𝑲+ ∙𝑲𝒐𝒖𝒕 +𝑷𝑵𝒂+ ∙𝑵𝒂𝒐𝒖𝒕 +𝑷𝑪𝒍− ∙𝑪𝒍𝒐𝒖𝒕

Membrane diffusion potential depends upon three main factors:

1) Polarity of the electrical charge of the ion;
2) Membrane permeability (Р) for each ion;
3) Concentrations of ions inside (in) and outside (out) of cell
 The role of Na+-K+ ATPase in creating the
resting membrane potential
1. It pumps three Na+ ions out of the cell for every two K+ ions
pumped into the cell.
2. It creates and maintains the K+ concentration gradient, which
establishes the resting membrane potential.
 Ionic asymmetry between ECF and ICF

Due to pumps and channels activity

there is an ionic asymmetry at the both
sides of cell membrane.

Because of the large potassium

concentration gradient from inside
toward outside, there is a strong
tendency for extra numbers of
potassium ions to diffuse outward
through the membrane.

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 Rest membrane potential depends on:

• 1. Concentration gradient of ions;

• 2. Permeability of membrane for ions;
• 3. Charge of ion and direction its movements:
 When positive-charged ion leaves the cell the RMP becomes more
negative (for example, RMP was – 80 mv and became – 100 mv –
hyperpolarization);
 When negative-charged ion moves into the cell the RMP also becomes
more negative;
 When positive-charged ion moves into the cell the RMP becomes less
negative or positive (depolarization, for example, from – 90mv to +30
mv);
 When negative-charged ion leaves the cell the RMP also becomes less
negative (Cl ions);
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 Conclusions:

 At rest a membrane is almost impermeable for the Na+ and Cl-

ions, because of this, K+ ions mainly contribute to the Rest
Membrane Potential.
 К+ ions go out from the cell into the extracellular fluid through
the membrane “leaking channels” down their concentration
gradient.
 The large organic anions are not able to pass through the
membrane and leave the cell. They form negative charge inside
the cell.
 Positively charged K+ ions, that leave the cell form additional
electronegativity in the cytoplasm.
 Na+/K+ pump restores ionic gradients across the membrane and
ensure the continuity of ionic current across the cell membrane.
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 Action Potential

• The action potential (AP) is a phenomenon of

excitable cells and consists of a rapid depolarization
(upstroke) followed by repolarization of the
membrane potential.
• Action potential is the basic mechanism for
transmission of information in the nervous system
and in all types of muscle
 Terminology
• Depolarization is the process of making the membrane potential less negative or it may
even cause the cell interior to become positive.
• Hyperpolarization is the process of making the membrane potential more negative.
• Inward current is the flow of positive charge into the cell thus, it depolarizes the
membrane potential.
• Outward current is the flow of positive charge out of the cell thus, it hyperpolarizes the
membrane potential.
• Threshold potential is the membrane potential at which occurrence of the action potential
is inevitable.
• Overshoot is that portion of the action potential where the membrane potential is positive
(cell interior positive).
• Undershoot, or hyperpolarizing afterpotential, is that portion of the action potential,
following repolarization, where the membrane potential is actually more negative than it is
at rest.
• Refractory period is a period during which another normal action potential cannot be
elicited in an excitable cell. Refractory periods can be absolute or relative.
 All-or-none response
An action potential either occurs or does not occur

• If an excitable cell is depolarized to threshold, then

the occurrence of an action potential is inevitable.
• If the membrane is not depolarized to threshold, no
action potential can occur.
• If the stimulus is applied during the refractory period,
then either no action potential occurs, or the action
potential will occur but not have the stereotypical
size and shape.
An action potential of nerve
1- slow depolarization
2 - threshold or critical
level of depolarization
3 - upstroke of the
action potential (rapid
depolarization)
4 - overshoot
5 - repolarization
6 - hyperpolarizing
afterpotential
(undershoot).
 Voltage-Gated (Fast) Na+ Channels
The opening of these channels is responsible for the rapid depolarization phase (upstroke) of
the action potential. The fast Na+ channel has 2 gates and 3 conformational states.

• Closed: the activation gate (m-gate) is closed

and the inactivation gate (h-gate) is open. Na+
conductance (g) is low.
• Open: both gates are open and thus Na+ g
increases causing depolarization
• Inactivated: the activation gate is open and
inactivation gate (h-gate) is closed.
• Once the cell repolarizes, the fast Na+ channel
transitions back to the closed state, and is thus
ready to reopen to cause another action
potential.
Once an Na+ channel inactivates, it cannot go
back to the open state until it transitions to the
closed state
 Mechanism of Action Potential
An action potential occurs if threshold is reached

1. Rest state: value of RMP is -70 - -80 mv, sodium voltage-gated channels are
closed, potassium ions leave the cell through the leaking channels, sodium-
potassium pump keeps ionic asymmetry;
2. Action of threshold or suprathreshold stimulus leading to destabilization of
electrical field of cell membrane;
3. In the region of stimulation the sodium-voltage-gated channels are activated
(opened);
4. Sodium ions enter and cause partial depolarization of its membrane – local
response (slow depolarization, partial depolarization) ;
5. Potential must reach the CLD (threshold) which is minimum needed for
opening of all the sodium voltage-gated channels (CLD is about – 60 mv for
most of the cells);

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 Mechanism of Action Potential
6. Resulting in sudden conformational changes in m-gates of sodium
channels pushing them to the open position – activated state;
7. As rising MP passes 0 mv, sodium gates are inactivated and begin closing;
8. By the time they all close and sodium inflow ceases;
9. The voltage peaks at approximately +30 mv the membrane is positively
charged inside and negatively outside – polarity is reversed compared to
the RMP;
10. At the same time potassium channels opened and potassium diffuses
rapidly out of the cell resulting in repolarization and hyperpolarization;
11. After that, the voltage-gated channels restore their native conformation
and Na/K – pump acts to restore concentration gradient of both ions

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 Key Points

• The action potential is all or none:

• Occurs if threshold is reached, doesn’t occur if threshold
is not reached.
• The action potential cannot summate.
• Under normal conditions, the action potential
regenerates itself as it moves down the axon, thus it is
propagated (magnitude is unchanged).
 An action potential doesn’t occur if threshold is
not reached
• The degree of depolarization is related to the magnitude of the stimulus.
• The membrane repolarizes (returns to rest).
• It can summate, which means if another stimulus is applied before repolarization
is complete, the depolarization of the second stimulus adds onto the
depolarization of the first (the 2 depolarizations sum together).

Subthreshold stimulus
↓
Subthreshold response
(local response,
partial depolarization)
BUT NOT Action Potential
Refractory Periods
• The absolute refractory period is the period
during which no matter how strong the
stimulus, it cannot induce a second action
potential because during this time, most fast
Na+ channels are either open or in the
inactivated state (can not get opened)
• the length of this period determines the
maximum frequency of action potentials.
• The relative refractory period is that period
during which a greater than threshold
stimulus is required to induce a second
action potential.
• The mechanism for this is the elevated K+ g.
 Self-control
• For a summer research project, a second-year medical student is
introduced to the patch clamp technique in a neurophysiology
laboratory. As part of her training, she learns to monitor both
membrane potential and individual channel function. At the end for
the summer, she is able to write up the specific techniques and
findings from monitoring action potentials.
• Which of the following ionic changes is correctly matched with a
component of the action potential?
• A. Opening of voltage-gated K+ channels: after-hyperpolarization
• B. A decrease in extracellular Ca2+: repolarization
• C. Opening of voltage-gated Na+ channels: depolarization
• D. Rapid closure of voltage-gated Na+ channels: resting membrane
potential
• E. Rapid closure of voltage-gated K+ channels: relative refractory
period
• C. Opening of voltage-gated Na+ channels:
depolarization
Thank you for your attention