Beyond voltage‐gated ion channels: Voltage‐operated membrane proteins and cellular processes

Abstract

Voltage-gated ion channels were believed to be the only voltage-sensitive proteins in excitable (and some non-excitable) cells for a long time. Emerging evidence indicates that the voltage-operated model is shared by some other transmembrane proteins expressed in both excitable and non-excitable cells. In this review, we summarize current knowledge about voltage-operated proteins, which are not classic voltage-gated ion channels as well as the voltage-dependent processes in cells for which single voltage-sensitive proteins have yet to be identified. Particularly, we will focus on the following. (1) Voltage-sensitive phosphoinositide phosphatases (VSP) with four transmembrane segments homologous to the voltage sensor domain (VSD) of voltage-gated ion channels; VSPs are the first family of proteins, other than the voltage-gated ion channels, for which there is sufficient evidence for the existence of the VSD domain; (2) Voltage-gated proton channels comprising of a single voltage-sensing domain and lacking an identified pore domain; (3) G protein coupled receptors (GPCRs) that mediate the depolarization-evoked potentiation of Ca mobilization; (4) Plasma membrane (PM) depolarization-induced but Ca -independent exocytosis in neurons. (5) Voltage-dependent metabolism of phosphatidylinositol 4,5-bisphosphate (PtdIns[4,5]P , PIP ) in the PM. These recent discoveries expand our understanding of voltage-operated processes within cellular membranes.

Structure and electromechanical coupling of a voltage-gated Na+/H+ exchanger

“…1b ). The S4 VSD renders SLC9C1 a transporter that is activated only in response to hyperpolarization (−95 mV), and the CNBD bind cAMP to enable SLC9C1 to become activated closer to the resting membrane potential of sperm (−50 mV) 2 VSDs are thought to have evolved independently from ion channels, and there are a few examples of non-channel VSD domains coupled to soluble enzymes 1 . However, the coupling of a S4 VSD to a transporter appears to be unique to SLC9C1.…”

“… Voltage-sensing domains control the activation of voltage-gated ion channels, with a few exceptions 1 . One such exception is the sperm-specific Na + /H + exchanger SLC9C1, which is the only known transporter to be regulated by voltage-sensing domains 2 – 5 .…”

Measuring Absolute Membrane Potential Across Space and Time

“…Nevertheless, all membrane-localized proteins experience V mem , and more of these proteins may be sensitive to V mem than was previously thought. Evidence of V mem sensitivity exists for various membrane components (121), including phosphatases (80), G protein-coupled receptors (92,93), and the membrane organization itself (123). For most systems, we have an incomplete understanding of both the determinants of V mem and the factors that respond to V mem .…”

Arachidonic acid hyperpolarizes mesenchymal stromal cells from the human adipose tissue by stimulating TREK1 K+ channels

“…The common pathway is the voltage-dependent regulation of ion channels and electrogenic transporters, which mediate fluxes and therefore intracellular concentrations of metabolites and important regulatory ions, Ca 2+ and H + first of all. It also has been recognized that membrane voltage can affect cellular functions by modulating ligand binding to G-protein-coupled receptors (GPCRs) and coupling thereof to G-proteins as well as by regulating voltagesensitive enzymes and altering the metabolism of phosphatidylinositol 4,5-bisphosphate (PIP 2 ) [8].…”