Voltage-gated sodium channels and their roles in drug action

Abstract

Summary The voltage-gated ion channels (VGICs) represent a superfamily of glycoprotein molecules that are able to form membrane spanning channels that ‘gate' in response to changes in membrane potential. This regulates ion selective fluxes on the microsecond–millisecond timescale. They are crucially involved in regulating activity in excitable cells of the CNS and in skeletal muscle fibres. VGICs are directly involved in control of cellular resting potential, neurotransmitter release, determination of spike firing threshold and initiation, propagation and shaping of action potentials. They represent a major target for local anaesthetic, anti-convulsant/analgesic and anti-arrhythmic drugs. The basic mechanism for communication of information between the cells of the CNS is the firing of action potentials. The action potential is an ‘all or none' cellular response that is highly dependent upon a range of VGICs which are transiently permeable to Na + (cation influx depolarises the cell), K + (efflux for rapid repolarisation and refractoriness) and perhaps to a lesser extent Ca 2+ ions (these are important in regulating action potential duration, contractility, transmitter release etc). In order to encode the large volume of information being processed by the CNS, action potentials are often fired in very complex and high-frequency patterns. The role of VGSCs in the control of cellular excitability and determining the pattern of cellular communication within the CNS makes them potential targets for contribution to the clinical state of anaesthesia (although this is highly controversial). In this review we will endeavour to explain the physiological roles of voltage-gated sodium channels, their molecular classification, structure and modulation by drugs.