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Lecture 1: “Resting membrane potential, action potential and their

mechanisms”

Plan

1. Physiology as a theoretical basis for the medical profession

2. Resting membrane potential and mechanisms of its establishment
3. Action potential and its ionic mechanisms
4. Graded potential and its features
5. Mechanism of conduction of the action potentials

Hello! Welcome to the lecture in Physiology.

My name is Professor Volodymyr Feketa. I will teach you physiology and will
lecture on this subject.
Each lecture will be divided into several parts. You can see the plan for today's
lecture on the slide. And you can write it down in your notebook.
Let's start with the first item
Physiology as a theoretical basis for the medical profession

Physiology is a branch of medicine that studies the functions of the human body, the
underlying physiological processes and mechanisms of their regulation.
So I would like to explain to you the 3 key terms related to physiology
Function can be defined as - the achievement of a desired outcome for the body
For example,
The function of the heart is to provide a closed-loop circulation of blood
through the vascular system
The function of the lung is to provide gas exchange between blood and the
external air
The function of the Kidney is to purify the blood from toxins by urine
excretion and so on
But if you look more closely at the function of these organs, you can see that they are
achieved by the interaction of various processes
Let's take the heart, for example
Initially, the sinus node in the right atrium generates rhythmic excitations that define
the heart rate. Then, the nerve impulses are conducted by the conduction system to
the myocardium. And finally a reduction of the ventricles and ejection of blood into
the aorta and the pulmonary artery occurs.
Thus, we have 3 different processes – excitation, conduction and contraction, which
together interact and provide the main function of the heart – to pump blood through
the vascular system
If we consider the kidney, we can see that formation of the urine is achieved
also by three different processes: filtration of the blood in glomerulus, reabsorbtion of
nutrients, water and needed salts into the blood and excretion of toxins from the
blood into urine. Secondary urine is formed as a result of these processes.
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All these examples show us that a function is achieved by interaction of
various underlying processes. But why must a physician know not only the function
of different organs but also – the underlying processes ? When the function is
impaired, the cause can only be established by analysis of the underlying processes.
In case of the heart diseases, for example, circulatory disorder may be associated with
arrhythmias as well as a destruction of the conduction system, or - with a decrease in
myocardial contractility. Violation of each of these processes results in a disturbance
of cardiac function , but all these cases require a different treatment.
And now let's talk about the regulating mechanisms of the function. They are
needed for instant adaptation of the function to the changes in external and internal
environment.
For example, if a human is in a rest state or a sleeping state – his heart
contracts slowly, his arterial blood pressure and cardiac output are relatively low. But
if he exercises, all these indexes rise depending on his load. The nervous and
endocrine systems – two main regulatory systems – have many tools to fit the heart
function to the new metabolic demand of the body. We can mention among them
activation of the sympathetic nervous system, the hormones epinephrin and cortisol,
and many other mechanisms. We will study them during this course.
Why should the physician be aware of these mechanisms? The answer to this
question is very simple. Because the treatment of disease is nothing more than a
correction of the natural mechanisms of regulation with drugs and non-drug methods.
I hope I have convinced you to study the physiology and to use this knowledge
as a theoretical basis of your profession.
The second item of today’s lecture plan is
Resting membrane potential and mechanisms of its establishment
At first, please write down the definition of this concept:
The Resting membrane potential is a potential difference between the outer
and inner sides of the cell membrane in excitable tissues.
This difference can be observed in the nerve, muscle,. and secretory cells.
If you put one electrode at the outside of the cell membrane and the other one - inside
the cell, the oscilloscope will show the potential difference between them of about
minus 70 millivolts. At the same time negative charges predominate inside the cell,
and positive - on the outer side of the membrane. How can we explain this
asymmetry of the charges across the cell membrane? In order to do this we have to
consider some important features of the cell membrane.
The main features are ion channels and Sodium-Potassium pump.
There are two types of ion channels: passive channels and active channels.
Passive channels (or leak channels) are always open, and ions can move freely across
them. Active channels have gates through which ions can move only if they are open,
but most of the time they are closed. Depending on the mechanism of opening the
gates, active channels are divided into 2 subtypes Ligand-gated ion channels and
Voltage-gated ion channels. A ligand is a molecule that binds to a receptor. A
receptor is a protein that has a site to which a ligand can bind. When a ligand binds
to the receptor site, the ion channel opens or closes. For example, the
neurotransmitter acetylcholine released from the presynaptic terminal of a neuron is a
chemical signal that can bind to a ligand-gated Na+channel in the membrane of a
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muscle cell. As a result, the Na+channel opens, allowing Na+ to enter the cell.
Ligand-gated ion channels exist for sodium Na+, Potassium K+, Calcium Ca2+, and
Clorine Cl−, and these channels are common in tissues such as nervous and muscle
tissues, as well as glands.
Voltage-gated ion channels open and close in response to small voltage
changes across the plasma membrane. The movement of ions into or out of the cell
changes the charge difference across the plasma membrane, which causes voltage-
gated ion channels to open or close. This subtype of the channels is responsible for
action potential.
Na-K pump is a membrane protein, that uses energy from ATP for moving
Na+and K+ through the plasma membrane against their concentration gradients.
Sodium ions are transported out of the cell, increasing the concentration of
Na+outside the cell, and potassium ions are transported into the cell, increasing the
concentration of K+ inside the cell. Approximately three sodium ions are transported
out of the cell and two K+ions are transported into the cell for each ATP molecule
used.
So, Na-K pump creates ionic asymmetries on both sides of the cell membrane.
Potassium concentration inside the cell is about 30-40 times higher than in the
extracellular space, and sodium about 10-15 times lower than outside the cell.
In rest state only leak channels are open and ions can move across the
membrane according to their concentration gradient. Because most leak channels are
K –channels, cell membrane is mostly permeable to K ions, that move outside the
cell.
However, the force of electrostatic interaction with the negatively charged ions
inside the cell counteracts with K outflow. This force is called electrochemical
gradient. When electrochemical gradient and concentration gradient become equal –
a big amount of positively charged K-ions are located on the external side of the cell
membrane and there is an excess of negatively charged ions (mostly protein anions)
inside the cell. A charge difference between outer and inner sides of the cell
membrane is called equilibrium K-potential. It is about minus 90 millivolts.
Potassium equilibrium potential can be calculated using the Nernst formula
As you can see, it depends on ratio of Ci over Co (Ci/Co) , where Ci is the
concentration of Potassium inside the cell and Co is the concentration of Potassium
outside the cell.
However, the cell membrane is somewhat Ci
permeable to sodium ions, and these E  61 lg
K
positively charged ions move into the cell С o
according to their concentration and
electrochemical gradient and as a result a potential difference between the outer and
inner sides of the cell membrane becomes about -70 mV.
This difference is called the resting membrane potential.
The major ionic influence on the resting membrane potential is due to the movement
of K+ through leak channels. Other ions, such as Sodium+ , have only a minor
influence on the resting membrane potential because there are relatively few leak
channels for them. Even after the resting membrane potential is established, however,
cells gradually lose Potassium+ and gain Sodium+ . The large concentration gradients
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for Na+ and K+ would eventually disappear without the continuous activity of the
Sodium+Potassium+ pump.
And now let's move on to the third item of this lecture plan.
Action potential and its ionic mechanisms.
When the stimulus acts on the cell membrane, it opens the voltage-gated sodium
channels for a short period of time (about 0-point-2 - 0.5 milliseconds). As a result
positively charged sodium ions move into the cell and potential difference is
reversed. Now the outer side of the cell membrane is charged negatively and its inner
side – positively. This phase of the developing action potential is called –
depolarisation. As soon as the difference reaches 30 mV, sodium channels are
closed, and the slow voltage-gated potassium channel are opening. At the same time,
leak potassium channels remain open all the time. All these events cause the outflow
of Potassium ions from the cell and return the membrane potential to basal level. This
phase is called repolarisation. Because of a lower density of the sodium channels
compared to potassium, the repolarisation phase lasts a little longer than -
depolarisation. Voltage-gated Potassium channels start closing when the membrane
potential returns to the level of the membrane rest potential. But this process is
relatively slow and extra amount of Potassium ions that move out of the cell creates a
third phase of the action potential - afterhyperpolarisation.
An action potential occurs only if the stimulus is able to depolarize the cell
membrane to the threshold level. Such stimuli are called the threshold stimuli. The
threshold level is about of 15-25 millivolt lower then the membrane rest potential for
most excitable cells. Action potentials occur according to the all-or-none principle. If
a stimulus can depolarize the cell membrane to threshold level, the action potential
with the maximum possible amplitude evolves. If the stimulus is not sufficient to
reach the threshold, action potential doesn’t occur at all. The cell can’t react at all to
the stimuli during the depolarisation and repolarisation phase. This period of time is
called the absolute refractory period. The afterhyperpolarisation phase corresponds to
the relative refractory period, when the cell can react only to the supraliminal stimuli.

Now let’s talk about the graded potential and its features. It is the next part
of the lecture.
The graded potential evolves if subliminal stimulus is applied to the cell membrane.
Only a few ionic channels are opening and small changes of the membrane potential
occur. These changes can be classified as the local depolarisation and the local
hyperpolarisation. The local depolarisation occurs if the sodium channels are opened
and local hyperpolarisation – if the potassium or chloride channels are opened. When
the strength of the stimulus rises (but remains lower then threshold level )- the size of
the graded potential is rising too. This interdependence is known as the strength
principle. Graded potential can’t spread over the cell membrane and it remains local.
Graded potential can be summed up in two ways. The first way is called the temporal
summation. It can be observed if a series of stimuli is applied to the cell. If temporal
intervals between a single stimulus are short (10-15 milliseconds) then more and
more channels are opened and the ionic currents arise. The second way is called
spatial summation. It can be observed if two and more stimuli are applied to the cell
simultaneously.
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The final point of today’s lecture is The mechanism of conduction of the
acting potentials.
In contrast to the graded potential, action potential can spread along the cell
membrane remaining the same size. A maximal velocity of the conduction is
observed in the myelinated nerve fibers. It reaches about 120 meters per second.
Mechanism of the conduction in the unmyelinated nerve fibers is achieved by a
local ionic current between excited area and the neighboring unexcited area. These
areas have the different charge because of the influx of sodium ions in the
depolarisation phase. The local current acts as the threshold stimulus for the next
unexcited area and the action potential moves continuously along the cell membrane.
In the myelinated nerve fibers the impulse jumps from one Ranvye node to
another. Such a form of conduction is called the saltatory conduction. It is not only
faster, but also more efficient, compared to the continuous conduction. The myelin
sheet prevents the active and passive transport of ions. Therefore, the myelinated
areas don’t waste energy for the establishment of the membrane rest potential.