Voltage-gated sodium channels operate via specific conformational changes triggered by membrane depolarization
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Peer-reviewed literature details that membrane depolarization triggers voltage-sensor activation, leading to specific conformational changes such as linker movement and pore occlusion in voltage-gated sodium channels.
Voltage-gated sodium channels initiate action potentials and control electrical signaling throughout the animal kingdom. Fast inactivation is an essential auto-inhibitory mechanism and requisite component of sodium channel physiology. Recent structural and electrophysiological results are inconsistent with the canonical ball and chain model of fast inactivation thus necessitating an updated theoretical framework. Here, we use encoded fluorescence spectroscopy and high-resolution electrophysiology to capture key steps in the fast inactivation mechanism, from voltage-sensor activation to pore occlusion, an ultra-fast process which occurs in less than 2 milliseconds. Upon depolarization, activation of the domain IV voltage sensor initiates cytoplasmic DIII_DIV linker movement and quickly repositions the IFM motif into a hydrophobic pocket adjacent to the pore. This triggers a structural rearrangement of the pocket. The phenylalanine of the IFM motif contacts the pore-forming helices via a hydrophobic interaction with S6 of DIV and an aromatic/hydrophobic interaction with S6 of DIII. These two interactions occur only after both S6 segments rotate, thus exposing the hydrophobic gate into the pore producing the fast inactivation. Based on the current results, we propose an alternative lock and key model to explain the molecular mechanism of fast inactivation.
The Croonian Lecture, 1983. Voltage-gated ion channels in the nerve membrane. In the Croonian Lecture for 1957, Sir Alan Hodgkin described the role of the channels selective for sodium and potassium ions in the conduction of the nervous impulse. An essential feature of these channels is the manner in which the complex kinetics of their opening and closing is controlled by the electric field across the membrane, and the purpose of the present lecture is to consider the advances that have been made in the past 25 years towards an understanding of the underlying molecular mechanisms. One such advance has been the successful recording, independently of the ionic currents, of the small asymmetry current known as the gating current, that accompanies the conformational changes that take place in the sodium channels. A quantitative analysis of the characteristics of the gating current suggests that activation is brought about by two more or less independent processes operating in parallel, to one of which the slower mechanism of inactivation is coupled sequentially.
A new look at the mechanism of activation and inactivation of voltage-gated ion channels. Studies on the kinetics of activation and inactivation of the sodium channels of the squid giant axon, on the sodium gating current, and on the properties of the non-inactivating steady-state current, are briefly reviewed. Taken in conjunction with recent evidence on the structure of voltage-gated ion channels, they have led to the development of a series-parallel model of the sodium channel that can be regarded as a modernized version of the Hodgkin-Huxley model, with some novel features. It is suggested that activation results from conformational changes brought about by the four S4 voltage sensors operating in parallel, each of which makes two discrete steps to reach the fully activated state of the channel. There follows a voltage-independent hydration step, and the channel is ready to open.
These results indicate that there is a kinetic basis for the selectivity of voltage gated channels and suggest that other types of channels may operate by related mechanisms. The focus of the surface compartment model on charged surfaces has led to a description of the channel opening/closing process in terms of surface free energy, assuming an analogy to the aggregation/disaggregation reactions in oligomeric proteins. The opening of voltage gated oligomeric channels can be formulated in terms of variations in the surface free energy that are triggered by changes in the surface charge density. On this basis, it is possible to introduce gating phenomena into the surface compartment model and to couple the channel processes with charge movements. Published in Biochimica et biophysica acta (1987)
depolarizing neuromuscular blockers, when depolarization is triggered, voltage-gated sodium channels are activated due to sensing the depolarization from
Neuromuscular drugs are chemical agents that are used to alter the transmission of nerve impulses to muscles, causing effects such as temporary paralysis of targeted skeletal muscles. Most neuromuscular drugs are available as quaternary ammonium compounds which are derived from acetylcholine (ACh). This allows neuromuscular drugs to act on multiple sites at neuromuscular junctions, mainly as antag
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