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Deciphering voltage-gated Na(+) and Ca(2+) channels by studying prokaryotic ancestors.

ABSTRACT: Voltage-gated sodium channels (NaVs) and calcium channels (CaVs) are involved in electrical signaling, contraction, secretion, synaptic transmission, and other physiological processes activated in response to depolarization. Despite their physiological importance, the structures of these closely related proteins have remained elusive because of their size and complexity. Bacterial NaVs have structures analogous to a single domain of eukaryotic NaVs and CaVs and are their likely evolutionary ancestor. Here we review recent work that has led to new understanding of NaVs and CaVs through high-resolution structural studies of their prokaryotic ancestors. New insights into their voltage-dependent activation and inactivation, ion conductance, and ion selectivity provide realistic structural models for the function of these complex membrane proteins at the atomic level.

SUBMITTER: Catterall WA

PROVIDER: S-EPMC4553089 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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Deciphering voltage-gated Na(+) and Ca(2+) channels by studying prokaryotic ancestors.

Catterall William A WA Zheng Ning N

Trends in biochemical sciences 20150805 9

Voltage-gated sodium channels (NaVs) and calcium channels (CaVs) are involved in electrical signaling, contraction, secretion, synaptic transmission, and other physiological processes activated in response to depolarization. Despite their physiological importance, the structures of these closely related proteins have remained elusive because of their size and complexity. Bacterial NaVs have structures analogous to a single domain of eukaryotic NaVs and CaVs and are their likely evolutionary ance ...[more]

PMID: 26254514

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Project description:Propofol is widely used in the clinic for the induction and maintenance of general anesthesia. As with most general anesthetics, however, our understanding of its mechanism of action remains incomplete. Local and general anesthetics largely inhibit voltage-gated Na+ channels (Navs) by inducing an apparent stabilization of the inactivated state, associated in some instances with pore block. To determine the biophysical and molecular basis of propofol action in Navs, we investigated NaChBac and NavMs, two prokaryotic Navs with distinct voltage dependencies and gating kinetics, by whole-cell patch clamp electrophysiology in the absence and presence of propofol at clinically relevant concentrations (2-10 µM). In both Navs, propofol induced a hyperpolarizing shift of the pre-pulse inactivation curve without any significant effects on recovery from inactivation at strongly hyperpolarized voltages, demonstrating that propofol does not stabilize the inactivated state. Moreover, there was no evidence of fast or slow pore block by propofol in a non-inactivating NaChBac mutant (T220A). Propofol also induced hyperpolarizing shifts of the conductance-voltage relationships with negligible effects on the time constants of deactivation at hyperpolarized voltages, indicating that propofol does not stabilize the open state. Instead, propofol decreases the time constants of macroscopic activation and inactivation. Adopting a kinetic scheme of Nav gating that assumes preferential closed-state recovery from inactivation, a 1.7-fold acceleration of the rate constant of activation and a 1.4-fold acceleration of the rate constant of inactivation were sufficient to reproduce experimental observations with computer simulations. In addition, molecular dynamics simulations and molecular docking suggest that propofol binding involves interactions with gating machinery in the S4-S5 linker and external pore regions. Our findings show that propofol is primarily a positive gating modulator of prokaryotic Navs, which ultimately inhibits the channels by promoting activation-coupled inactivation.

Dataset Information

Deciphering voltage-gated Na(+) and Ca(2+) channels by studying prokaryotic ancestors.

Publications

Deciphering voltage-gated Na(+) and Ca(2+) channels by studying prokaryotic ancestors.

Similar Datasets

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