Introduction to Action Potential

Certain cells in the body are electrically active and can relay and sustain voltage fluctuations. These voltage fluctuations allow the propagation of signals and can be thought of as a means of communication between the cells. How these fluctuations come about is to a large extent dependent upon the cell membrane and the movement of ions across it. 

The cell membrane consists of a lipid bilayer structure that usually does not allow electrical ions to pass through freely. Therefore, there is a difference in ion concentration maintained across the cell membrane, causing it to be polarized. The maintenance of a potential across the cell membrane is called ‘membrane potential’. Usually, the inside of the cell is more negative than the outside, and the membrane potential is typically at -70 mV (millivolts). This is also described as the state of a normal resting membrane potential. 

The membrane structure also harbours certain ion transporters that support the membrane potential. For example, potassium leak channels cause the escape of potassium ions from inside the cells. This is also supported by the fact that the intracellular fluid contains a high concentration of potassium ions compared to the extracellular environment, which consists of high concentrations of sodium and chloride ions. The high intracellular concentration of potassium creates a gradient for the efflux of potassium ions through the leaky channels, resulting in the formation of the negative resting membrane potential. The Na+/K+ ATPase pump, in response, helps to maintain the concentration gradient. 

Similarly, there are other channels embedded within the cell membrane that are responsible for the generation of an ‘action potential’

General Action Potential Physiology

An action potential is described as a sudden and spontaneous change or reversal in the membrane potential above a threshold value due to increased permeability of the cell membrane. Permeability of the membrane translates to the action of the ion channels in allowing certain ions to enter the cell, which would otherwise not be possible in the normal resting stage. 

The generation of an action potential depends upon the voltage-gated sodium channels, which exist in three states depending upon the phase of the action potential. 

Depolarization

The first phase of the action potential is the rising phase called ‘depolarization’, which occurs due to a stimulus and causes the opening of voltage-gated sodium channels. The stimulus could be in the form of a neurotransmitter released by the presynaptic cell that eventually binds to receptors on the postsynaptic cell membrane. The opening of the voltage-gated sodium channels causes an influx of sodium ions and increases the voltage. At this depolarization stage, the low membrane potential ceases, and the state of the voltage-gated sodium ions changes from a deactivated (closed) state to an activated (open) state. However, an action potential can only occur when depolarization reaches a threshold value of between -40 and -55 mV. 

Repolarization

The next phase of the action potential is the peak phase at which point the depolarization stops or reaches the highest point. Next begins the falling phase, called ‘repolarization’, where the sodium channels slowly start closing and more voltage-gated potassium channels open. The mechanism is a little less simple than that because potassium channels are open even during depolarization. However, during depolarization, the sodium influx is more than the potassium efflux, while the opposite is true for repolarization. The voltage-gated sodium channels that were once activated during depolarization also transition to an ‘inactivated’ state. 

Hyperpolarization

After repolarization, the membrane potential becomes more negative than the resting membrane potential for a short while. This phase is called ‘hyperpolarization’. Action potentials are not only generated by voltage-gated sodium channels. In animal cells, voltage-gated calcium channels cause calcium influx and generate different types of action potentials in cardiac and smooth muscle cells.

All-or-None Response

An action potential has an all-or-nothing property which means that any stimulus producing a lower than threshold potential will potentially result in no response, while a stimulus producing threshold potential will produce a full response in the excitable cell. Therefore, increasing the strength of the stimulus will not increase the strength of the action potential but rather increase the frequency of the action potential. This also means that once an action potential is propagated across an axon, its strength remains uniform. 

Refractory Periods

Although, after an action potential is generated, there might be a period where a larger than usual stimulus is needed to produce another action potential. This period is known as the relative refractory period. 

Similarly, an absolute refractory period denotes a state of inactivity of the sodium channels after an action potential. In this period an action potential cannot occur. 

Propagation of Action Potential

Propagation of an action potential has some differences in unmyelinated and myelinated axons. 

Propagation in a myelinated axon occurs through saltatory conduction where depolarization is not continuous but occurs in certain intervals along the axon, known as nodes of Ranvier. 

Unmyelinated axons propagate through continuous conduction where there is continuous depolarization along the length of the axon. 

Myelination in the central nervous system occurs through the Oligodendrocytes and in the peripheral nervous system through Schwann cells. Myelination imparts more velocity to the action potential and saves more energy by preventing leaking of the membrane. 

Cardiac Action Potential 

All cardiac cells are linked to each other through gap junctions that allow propagation of the action potential. However, there is a clear distinction between the cells that are capable of producing an action potential and cells that can only conduct it (i.e. ventricular myocytes). 

Cells that generate the action potential are called pacemaker cells and are found in the right atrium at the sinoatrial node. They exhibit automaticity. The phases of the cardiac action potential are also different from nerve action potentials. 

Resting Phase

The resting phase is at phase 4 where the outflow of potassium ions through leak channels establishes the negative resting membrane potential at -90 mV. The pacemaker cells, however, due to automaticity never remain at rest and have a pacemaker potential (-40 mV) at phase 4. The pacemaker potential is due to the passage of both K+ and Na+ into the cell by Hyperpolarization-activated cyclic nucleotide-gated channels. 

Read more about Muscle Contractions

Depolarization (Phase 0)

Depolarization occurs at phase 0 due to a fast-inward current via the influx of sodium ions. Another type of cells called the L-type calcium channels is mainly involved in the depolarization of pacemaker cells and also has a minor role in depolarizing non-pacemaker cells. The threshold potential is at -70 mV for non-pacemaker cells. 

Repolarization (Phase 1)

Next is Phase 1 where there is a small drop of voltage due to the inactivation of sodium channels and opening of transient outward K+ channels. Opening of these potassium channels allows a brief removal of potassium ions from the cell and produces a small notch of the action potential wave. 

Plateau (Phase 2)

Phase 2 is characterized by a plateau that prolongs the action potential. This is due to a balance between the outward flow by delayed rectifier potassium channels and inward flow by calcium channels. The L-type calcium channels causing the inward flow of calcium ions also bind to receptors on the sarcoplasmic reticulum (SR) called ryanodine receptors. This prompts more calcium ions released from the SR. 

Repolarization (Phase 3)

Repolarization in phase 3 occurs due to the closure of calcium channels and an outward flow of potassium by slow delayed rectifier potassium channels. The membrane potential becomes more negative and the potassium channel closes at a membrane potential of -85 to -90 mV. Certain ionic pumps then set the membrane potential back to resting membrane potential.

Electrocardiogram

The series of depolarization (contraction) and repolarization (relaxation) of the atrial and ventricular tissue can be registered through the electrocardiogram (ECG). The waveform that is generated can be divided and attributed to the contraction and relaxation of specific areas of the heart. 

For example, the p wave represents the depolarization of the atria. 

The QRS complex represents the depolarization of the ventricles, while the Q wave represents the repolarization of the ventricles. 

Repolarization of the atrium coincides with the QRS complex, so it cannot be seen on the ECG. 

Phases of the cardiac action potential can also be correlated with the ECG. Phase 0 and 1 are the QRS complex. Similarly, the ST segment is representative of Phase 2, while the T wave is representative of Phase 3. 

Role of Action Potential

An action potential can be generated in different types of cells in the body, facilitating their unique functions. It has a locomotive function at the neuromuscular junction and helps in the contraction of cardiac and smooth muscles. At the neuromuscular junction, an action potential on reaching the presynaptic axon terminal resultantly releases acetylcholine. 

Acetylcholine is a neurotransmitter that is involved in the depolarization of the motor endplate. The ensuing depolarization eventually enters the cytosol through T tubules and causes the sarcoplasmic reticulum to release calcium ions. The calcium ions interact with troponin in the sarcomere and produce the excitation-contraction coupling. Voluntary muscle contraction occurs through this mechanism. 

Action Potential in Non-Muscular cells

There are many other types of cells that can generate an action potential, including the glomus cell and endocrine cells. 

Glomus Cells

Glomus cells are located in the peripheral chemoreceptor organs called carotid bodies These cells are interoceptors that are capable of transducing a stimulus within the body into an action potential. More specifically, they respond to changes such as a decreased partial pressure of oxygen (hypoxia), increased partial pressure of carbon dioxide (hypercapnia), or a decreased pH (acidity). 

When such a stimulus is present which enables depolarization of glomus cells, voltage-dependent calcium channels are activated that allow calcium ions to enter. Intracellular calcium ions cause action potentials in the afferent nerve endings through the release of neurotransmitters. The afferent nerve fibres communicate with the brain to produce the desired effect. For example, a hyperventilation response is desired in the case of hypoxia. 

Action potentials produced by neurons enable oxytocin to be produced and released in the circulation due to certain stimuli such as a baby suckling or during labour. In response to glucose, the β-cells of the islet of Langerhans also undergo depolarization and release insulin. 

Clinical Significance

Following are some clinical conditions associated with an action potential. 

Long QT Syndrome

In the heart, long QT syndrome (LQTS) can result from mutations in the calcium and sodium channel genes. These mutations cause prolonged depolarization and an increase in the QT interval of the cardiac cells’ action potential. 

Myasthenia Gravis

Myasthenia gravis is an autoimmune disorder of the neuromuscular junction which prevents cell membrane depolarization due to autoimmunity against nicotinic acetylcholine receptors (nAChR). Loss of the receptor causes the failure of depolarization of the muscle cells. The resultant symptoms of the patients include generalized muscle weakness and hypotonia. 

These pathologies are called channelopathies because they affect ion channels that rapidly depolarize excitable tissues. 

Effect of Toxins

Certain toxins also act in ways to prevent an action potential at the junction. 

For example, Botulinum toxin cleaves intracellular SNARE proteins. These proteins are responsible for releasing acetylcholine into the synaptic cleft. Therefore, nerve signalling is affected and paralysis occurs. 

Similarly, Saxitoxin binds to voltage-gated sodium channels, causing muscle weakness and ataxia. In severe cases, some pathologies can even lead to respiratory failure, hypotension, and death. 

Demyelinating Diseases

As mentioned before, myelination increases the speed of conduction of action potential. Demyelinating diseases are a set of diseases caused by multiple factors such as viral infections, metabolic, physical, and hypoxic causes. Due to loss of myelin, nerve conduction is affected, causing symptoms like numbness, loss of reflexes and uncoordinated movements, etc.

Action of Certain Drugs

Antiarrhythmic Drugs

Drugs acting on the cardiac action potential are used as antiarrhythmic drugs. Classification of these antiarrhythmic drugs includes class 1 sodium channel blockers which work on atrial and ventricular myocytes and slow the phase 0 depolarization. Class III drugs affect potassium channels and prolong action potential duration. Class IV drugs decrease the rate of automaticity by blocking calcium channels in cardiac pacemaker cells. Similarly, seizures caused by repetitive action potentials in the brain can be blocked by antiepileptic drugs. These drugs can either block the sodium channels or calcium channels. 

GABA Drugs

Similarly, drugs that act on the GABA receptors are used for anxiety disorders and seizures. One of these drugs includes diazepam which belongs to the benzodiazepine family of drugs. GABA is a neurotransmitter in the central nervous system. When released from the presynaptic cell, it binds to the GABA receptor on the postsynaptic cell and causes it to hyperpolarize. This reduces the excitatory effects of other neurotransmitters.

Frequently Asked Questions

What is resting membrane potential?

Due to the selective permeability of the plasma membrane, a difference in the concentration of certain ions exists across the membrane. This causes a potential difference across the membrane known as resting membrane potential. This resting potential is maintained by maintaining the concentration of ions on two sides of the membrane. 

What is action potential?

Action potential is simply a transient change in resting membrane potential. When a stimulus acts on a cell, it changes the permeability of the membrane in such a way that positive ions move into the cell causing depolarization. The new potential thus developed is called action potential.

Why is action potential important?

Action potential is responsible for conduction of signals along the neurons. Nerve impulses travel along the neurons and other conducting fibres due to action potential. 

How action potential is generated?

In a resting state, a cell has more negative charges on the inside while more positive charges on the outside of the cell. So resting membrane potential is negative with respect to the outer environment of the cell. When a stimulus acts on the cell, membrane permeability changes in such a way that positively changed ions such as sodium ions move into the cell, causing depolarization of ‘negative’ resting potential. In this way, action potential is generated.

References 

1.  Lodish, H; Berk, A; Kaiser, C; Krieger, M; Bretscher, A; Ploegh, H; Amon, A (2000). Molecular Cell Biology (7th ed.). New York, NY: W. H. Freeman and Company. p. 695.
2.  Callies, C; Fels, J; Liashkovich, I; Kliche, K; Jeggle, P; Kusche-Vihrog, K; Oberleithner, H (June 1, 2011). “Membrane potential depolarization decreases the stiffness of vascular endothelial cells”. Journal of Cell Science. 124 (11): 1936–1942. doi:10.1242/jcs.084657. PMID 21558418.
3.  Marieb, E. N., & Hoehn, K. (2014). Human anatomy & physiology. San Francisco, CA: Pearson Education Inc.
4. Rang, H. P. (2003). Pharmacology. Edinburgh: Churchill Livingstone. ISBN 978-0-443-07145-4. Page 149