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Editorial: Molecular Mechanisms of Voltage-Gating in Ion Channels

Abstract : Editorial on the Research Topic Molecular Mechanisms of Voltage-Gating in Ion Channels Voltage-gated ion channels are transmembrane proteins conducting ions according to the electrochemical gradient, when opened by voltage. Hence, in these channels, at least one of the channel gates regulating the ion flux is controlled by the transmembrane potential. They are frequently ion specific and therefore selectively permeable to sodium (Na V channels), potassium (K V channels), calcium (Ca V channels) or chloride (CLC channels) ions. Depending on the channels, opening of the activation gate is triggered by membrane depolarization (e.g. K V , Na V and Ca V channels) or hyperpolarization (HCN channels for instance). In addition, in many voltage-gated channels, a so-called inactivation gate is also present. Compared to the activation gate, the latter is, when voltage-dependent, oppositely coupled to the potential: In K V , Na V and Ca V channels, upon membrane depolarization, the inactivation gate closes whereas the activation gate opens. Various voltage-dependent channels have been identified, depending on the excitable cell types in which they are expressed and their physiological role. They are characterized by their conductance, ion selectivity, pharmacology and voltage-sensitivity. These properties are mainly dictated by the amino-acid sequence and structure of the pore forming subunit(s), the presence of accessory subunit(s), the membrane composition and the intra-and extracellular ions concentrations. Many mutations have been identified in these channels, impacting their functions and provoking diseases named channelopathies. In 2012, we hosted a Research Topic on the Molecular Mechanisms of Voltage Dependency (Loussouarn and Tarek, 2012), bringing together scientists to collaborate and showcase the latest developments in the field. Since this Frontiers Research Topic, the development of new approaches, such as the use of cryo-electron microscopy (cryo-EM) at the atomic scale and the original approach of split channels, to name a few, has led to a more precise understanding of the mechanisms of voltage-gating, their targeting by toxins, and also their physio-pathological implications. Given the wealth of recent electrophysiological, biochemical, optical, and structural data regarding ion channel voltage-dependence, we felt there was clearly a need for putting together a new Research Topic that would include up to date Reviews and Original Research describing molecular details of the functioning of these complex voltage-gated channels. The review of Brewer et al. underlines how ion channel structures and models reveal critical differences in the atomic details of KCNQ1, hERG, and Na V 1.5 structures associated with their distinct voltage-gating and implication in Long QT syndrome, and also their pharmacological profiles. Such structural data may help defining the pathogenicity of the hundreds of variants in absence of functional data. It also mentions an important point: Molecular Dynamics represents a useful tool in refining cryo-EM structures, which are often of lower resolution in the periphery of protein core structures.
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Submitted on : Monday, September 20, 2021 - 9:51:43 AM
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Gildas Loussouarn, Mounir Tarek. Editorial: Molecular Mechanisms of Voltage-Gating in Ion Channels. Frontiers in Pharmacology, Frontiers, 2021, 12, ⟨10.3389/fphar.2021.768153⟩. ⟨hal-03348830⟩



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