Have you ever asked yourself how does your heart work? Why does muscle contraction occur? By what is our sexual attraction mediated? How does our skin react to touch and from where does pain occur? All these processes have one common feature of cells in our body - excitation.

Excitation is an active reaction of specialised (excitable) cells to external stimuli, which is manifested in the fact that the cell begins to perform specific functions inherent to it.

Excitable cells may exist in two discrete states which are rest (readiness to respond to external stimuli, to the perpetration of external work) and the state of excitation (active implementation of specific functions, the perpetration of external work). There are three types of excitable cells in the body which are nerve cells (excitation manifests in generation of electric impulse), muscle cells (excitation manifests in contraction), and excretory cells (through excitation there is emission of biologically active substances to intercellular space). Excitability is the cell's ability to move from a state of rest to a state of excitement by the action of the stimulus. Different cells have different excitability. Excitability in the same cell varies depending on the functional state.

# Excitable cell in a state of rest

The membrane of excitable cells are polarised. It means that there is a constant potential difference between the inner and the outer surface of the cell membrane, called the membrane potential (MP). At rest the MP value is -60 ... -90 mV (the inside of the membrane is negatively charged relative to the outside). Meaning MP cells at rest is called the resting potential (RP). MP cells can be measured by placing one electrode inside and the other outside the cell (Fig. 1 A)

[caption id="attachment_589" align="aligncenter" width="679"] Figure 1[/caption]

MP reduction relative to its normal level (RP) is called depolarisation, and increase is hyperpolarization. Repolarization is understood like baseline MP recovery after the change (see Fig. 1 B).

# Electrical and physiological manifestations of excitation

Let’s consider the various manifestations of excitation by the example of electric pulses stimulated cells (Fig. 2).

[caption id="attachment_591" align="aligncenter" width="565"] Figure 2[/caption]

Changes in membrane potential of cells (A) by the action of an electric current of varying strength.

Under the action of the weak (sub-threshold) electric pulses in the cell develops electronic potential. Electronic potential (EP) - the cell membrane potential’s shift, caused by a constant electric current. EP cells have a passive response to an electrical stimulus, the state of ion channels and ion transport is not changed. EP does not manifest a physiological response of the cell, so it is not excitation.

Under the action of a more strong sub-threshold current there occurs a prolonged MP’s shift which is called the Local Answer (LA). The LA is the active cell’s reaction to the electrical stimulus, but the state of ion channels and ion transport in this case varies slightly. LA does not show appreciable physiological response of the cell. LA is called local excitation, because it is not covered by the excitation of the membranes of excitable cells which are around.

Under the action threshold and over-threshold current in the cell develops an action potential (AP). AP is characterized by the fact that the value of cell’s MP is very rapidly decreasing to 0 (depolarisation), and then the membrane potential becomes positive (from +20 to +30 mV), that is, the inner side of the membrane is positively charged relative to the outside. The value of MP quickly returns to its original level. Strong depolarisation of the cell membrane during development of AP leads to physiological manifestations of excitation (contraction, secretion, etc.). The action potential is called propagating excitation, since after emerging in the part of the membrane, it quickly spreads in all directions.

# The apparatus of the cell membrane of an excitable cell

In the excitation’s mechanisms four kinds of ions take part: K+, Na+, Ca++, Cl- (Ca++ ions are involved in the processes of excitation of some cells, such as cardiomyocytes, and the ions Cl- are important for the inhibition). The cell membrane, which is a lipid bilayer, is impermeable to these ions. In the membrane, there are two types of protein-specific integrated systems that allow the transport of ions through the cell membrane: ion pumps and ion channels.

# Ion pumps and transmembrane ion gradients

Ion pumps are integral proteins that provide the active transport of ions against a concentration gradient. Energy for transport is the energy of ATP hydrolysis. For example the Na+ or K+ pump (moves Na+ out of the cell in exchange for K+),  while the Ca++ and Cl- pump (pumps from the cell Ca++ and Cl- respectively).

As a result ion pumps are created and maintained transmembrane ion gradients. Thus the concentration of Na+, Ca++, Cl- intracellularly is lower than outside (in interstitial fluid) and K+ concentration inside the cell is higher than outside.

# Ion channels

Ion channels are integral proteins that provide passive transport of ions along the concentration gradient. Energy for transport is the difference in concentration of ions on either side of the membrane (transmembrane ion gradient). Non-selective channels have the following properties. They allow to pass all types of ions, but the permeability for the K+ ions is considerably higher than for other ions and they are always open. While selective channels allow only one type of ion, for each type of ion channels has its own kind, and can be in one of three states: closed, activated, or inactivated.

The Channel’s selective permeability is provided by selective filter which is formed by a ring of negatively charged oxygen atoms, which are at the narrowest point of the channel. The changing of the channel status is provided by operation gating mechanism, which is represented by two protein molecules. They are also called as activation gate and  inactivation gate, by altering its conformation may overlap ion channel.

At rest, the activation gates are closed, inactivation gates are open (closed channel) [Fig. 3]. Under the action of portal system signal activation gates open and the transport of ions through the channel starts (channel is activated). With significant depolarisation of the cell membrane inactivation gates close and the transport of ions stops (channel inactivated). After restoring the levels of MP channel returns to its original (closed) position.

[caption id="attachment_594" align="aligncenter" width="711"] Figure 3 - Selective ion channel's status and conditions of transition between them[/caption]

Depending on the signal which causes the opening of the activation gates, selective ion channels are divided into chemo-sensitivity channels – signal to the opening  the activation gates is a conformational change associated with the channel receptor protein as a result of accession to the ligand, and potential-channels – signal to the opening of the activation gates  is a decrease  the MP (depolarisation) of the cell membrane to a certain level, which is called the critical level of depolarisation (CLD).

# Formation of the resting potential

Resting membrane potential is formed mainly through the exit of $latex K^+$ from cells through nonselective ion channels. Exit of positively charged ions out of the cell causes the inner surface of the cell membrane begins to be charged negatively relative to the outer.

Membrane potential resulting from the exit of $latex K^+$, called "equilibrium potential of K" (Ep). It can be calculated in Nernst equation: $latex E_K = \frac{R T}{F} \ln \frac{[K^+]_{out}}{[K^+]_{in}},$ where R is universal gas constant, T is temperature in Kelvin, F is Faraday's constant, $latex K^{+}_{out}$ is the concentration of $latex K^+$ ions outside the cell, $latex K^{+}_{in}$ is the concentration of $latex K^+$ ions inside the cell.

# Development of the action potential

There are several phases in the action potential (Figure 4): depolarisation phase; rapid re-polarisation phase; slow re-polarisation phase; hyper-polarization phase

[caption id="attachment_616" align="aligncenter" width="520"] Figure 4[/caption]

[caption id="attachment_617" align="aligncenter" width="520"] Figure 5[/caption]

Fig. 2.4. Changing of the membrane potential, the intensity of $latex K^+$ and $latex Na^+$ transmembrane current and excitability of cell in different phases of the action potential.

D - depolarization phase, Pg - fast repolarization phase, Rm - slow repolarization phase, T – hyperpolarization phase;

N E –  period of normal excitability, Ra – absolute refractory period, R R - period of relative refractoriness, E+ - period of supernormal excitability, E- - period of subnormal excitability

Depolarization phase. Appearance AP is possible only by the stimulus that causes depolarization of the cell membrane. Depolarization of the cell membrane to a critical level of depolarization (CLD) cause avalanche opening of potential-depended Na+ -channels. Positively charged Na+ ions enter the cell on the concentration gradient (Na+ current), resulting in membrane potential rapidly decreases to 0, and then acquires a positive value. The phenomenon of changing the sign of the membrane potential is called reversion charge of the membrane.

Fast and slow phase of repolarization. The result of membrane depolarisation  is the opening potential-K + channels. Positively charged ions K + gets out of the cell by the concentration gradient (K+ currents), which leads to recovery of the membrane potential. At the beginning of phase the intensity of  K+ current is high and repolarization occurs quickly, by the end of phase intensity decreases, and repolarization slows.

Hyperpolarization phase develops due to residual potassium current and due to direct effect of activated electrogenic Na + / K + pump.

Overshoot - period of time during which the membrane potential has a positive value.

Threshold potential - the difference between the resting membrane potential and the critical level of depolarization. The threshold potential defines excitability of cell - the larger the threshold potential, the smaller the cell excitability.

Nature of cell's  response depends on sufficient threshold stimulus. When exposed to a sub-threshold value irritation response will not arise. Upon reaching the irritation threshold response occurs, it will be the same for any action threshold and supra-threshold stimulus value. This regularity is called the “Law of all or nothing”.

Thus, as soon as a cell has received an external stimulus and has responded to stimulation, inside her triggers a cascade of reactions designed to perform the functions of the cell, namely: Muscle cells - reduction, Glandular cells - secretions, synthesis of biologically active substances, and Nerve cells - nerve impulse generation.

Nerve cells are distinguished by one important function - conduction of nerve impulses in its appendages - the nerve fibres. During stimulation of the nerve fibres in his section in direct contact with the stimulus, an action potential appears.

Change of charge of the cell membrane leads to the potential difference between the excited and unexcited sections nerve fibers and, consequently, to an electric current directed from an excited portion to an unexcited. So irritation of the skin or internal organs by inflammation or damage is  transmitted to the brain and felt like touch, pain, etc.