Neurological perspectives on voltage-gated sodium channels

Abstract

The activity of voltage-gated sodium channels has long been linked to disorders of neuronal excitability such as epilepsy and chronic pain. Recent genetic studies have now expanded the role of sodium channels in health and disease, to include autism, migraine, multiple sclerosis, cancer as well as muscle and immune system disorders. Transgenic mouse models have proved useful in understanding the physiological role of individual sodium channels, and there has been significant progress in the development of subtype selective inhibitors of sodium channels. This review will outline the functions and roles of specific sodium channels in electrical signalling and disease, focusing on neurological aspects. We also discuss recent advances in the development of selective sodium channel inhibitors.

Figure 1

Gating model and contribution of voltage-gated sodium channels to neuronal and cardiac action potential firing. Upper traces depict a cartoon representation of a whole-cell current clamp recording from a typical neuron (A) or cardiac myocyte (B). Dotted line indicates the resting membrane potential (V_m). Lower trace is temporally aligned to the upper trace and shows the change in sodium current (I_Na) during an action potential. Note a downward deflection of the trace reflects an inward movement of sodium ions into the cell. (1) At the resting membrane potential VGSCs are closed. A small depolarization of the neuronal membrane potential in response to sensory input or receptor input depolarizes the neuronal membrane potential to the threshold for VGSC activation (∼−50 mV). (2) VGSCs activate rapidly (∼1 ms to peak) allowing the influx of sodium and depolarizing the membrane potential further, forming the upstroke of the action potential. Note that the peak sodium current correlates with the peak of the action potential. (3) Following activation the sodium channels inactivate resulting in a decrease in sodium current and repolarization of the neuronal membrane potential, contributing to the downstroke of the action potential. Recovery from inactivation allows the channels to participate in the next action potential. (C) Mechanism of voltage sensitive gating of VGSCs. The left channel represents a VGSC in a deactivated (closed) state. A small depolarization of the membrane potential causes a movement of the positively charged S4 voltage-sensor domain (green) leading to a conformational change in the protein and opening of the pore (middle channel). Following activation, the pore is rapidly occluded by the inactivation gate, resulting in inactivation of the sodium channel (right channel).