Action potential

When an electric current is passed through the cellular membrane of an excitable cell, the charge separation and hence the membrane potential is perturbed. When the perturbation is small, the perturbed membrane potential is called a graded po- tential; it returns to the RMP via passive electro-diffusive processes. However, the electrogenic proteins spanning the membrane are sensitive to the membrane poten- tial and change their conductivity in response to this perturbation. This is called voltage-gating; it can lead to a further depolarisation, far exceeding the initial per- turbation, which is called an action potential (AP; Figure 1.2). Electrically excitable cells can generate both APs and graded potentials, while electrically inexcitable cells produce graded potentials only.

The production of APs results from the presence of a sufficient number of voltage-gated ion channels in the membranes of electrically excitable cells. If some fraction of the voltage-gated ion channels are blocked by specific pharmacological agents, the cells cannot produce APs. When these voltage-gated channels open, allowing passage of sodium or calcium ions, the membrane potential becomes less negative (more depolarised) and in some cases may even become positive. The AP ends in a return to the RMP mediated by several process, such as (i) the activation of specific potassium channels, which allows potassium ions efflux; (ii) the inactivation of sodium and calcium channels, preventing further sodium and calcium ions from crossing the membrane; (iii) the action of pumps restores the original cytosolic sodium and calcium ionic concentrations. The final phase may include a period during which the cell is hyperpolarised, that is, the membrane potential is more

negative than the RMP. -70 -50 +40 V ol ta ge (mV) Time (ms) Threshold Hyperpolarisation RMP Stimulus Action Potential Dep olari satio n R ep ola risa tio n Failed initiations 0 1 2 3 4 5 6

Figure 1.2: A schematic view of an idealised AP.The diagram illustrates the various

phases as the AP passes a point on a cell membrane.

Waveforms of APs

The amplitude of the AP tends to be in the range of 10 to 100 mV. This range is determined by the Nernst equilibrium potentials of the various permeant ionic species. Whereas there is relatively little variation in AP amplitude across various cell types, the time course does vary greatly, ranging from 1 ms in certain neurones, to 10 ms in skeletal muscle fibres, to the order of 0.5 s in cardiac muscle fibres, and many seconds in certain electrically excitable plant cells and in MSMCs [5]. Furthermore, APs can have many different shapes, as shown in Figure 1.3, which plots various membrane potentials as function of time at one particular point on the membrane.

Properties of action potentials

The threshold potential is a level to which the membrane potential must be depo- larised in order to initiate an AP (Figure 1.2). In other words, it is the value of the membrane voltage that needs to be attained in order that an AP can be generated. Physiologically, it is the membrane voltage at which the inward (sodium or calcium)

Figure 1: cc.

Figure 1.3: Many shapes of APs recorded from different cell types in different

animals. The horizontal dashed white line is zero potential. The top row compares the APs

in the squid giant axon as recorded (A) in the animal and (B) after isolation by dissection. (C) AP measured in the axon of a cell from a cats peripheral nervous system. (D) AP recorded from the cell body of a neuron from a cats spinal cord. (E) AP recorded from a muscle fibre in the heart of a frog. (F) AP recorded from a regulatory neuron in a sheeps heart. (G) Potential generated in the specialised muscle tissue that forms the electric organ of a fish that can shock its prey. (H) AP recorded from a more typical muscle from a frogs thigh. (from R.D.Keynes and D.J. Aidley [1])

current exceeds the outward (potassium) current, triggering a positive feedback cy- cle that defines the early part (rising phase) of the AP. If the threshold point is not reached, no AP will fire, but if the stimulus is above the threshold, an AP of maximum magnitude is triggered. For this reason, the AP is said to be all-or-none potential.

Immediately following an AP, a subsequent AP is less readily evoked; the cell is said to be refractory. For a brief interval (on the order of few milliseconds), called the absolute refractory period, a second AP cannot be elicited regardless of the intensity of the stimulus. Then for an interval greater than the absolute refractory period, there is a relative refractory period in which a second AP can be elicited, but with higher threshold. The refractory period is caused by the inactivation of sodium and calcium channels. These refractory periods indicate that the mechanism that generates the AP requires some time to recover.

Intercellular transmission of electric potential

After the triggering of an AP in a part of the membrane, the positive charges inside the cell will move to the adjacent region of the membrane causing the adjacent re- gion to depolarise too and thus the AP spreads. Membrane potential changes in one cell can result in membrane potential changes in adjacent cells. In certain tissues, including smooth and cardiac muscle, there exist specialised membrane junctions at which the membranes of adjacent cells are in close proximity. These communicat- ing junctions or gap junctions are composed of six connexin proteins that combine to form a cylinder with a pore in the centre region (Figure 1.4). The cytoplasms of adjacent cells are connected through this low resistance pathways. These path- ways allow direct passage for electrical, chemical, and metabolic signalling between cells [32–35]. Hence, if a current is injected into a cell in a tissue, a fraction of this current is coupled via gap junctions to the adjacent cells. Gap junctions are found in tissues where synchronisation of electrical activity of many cells occurs [5].