Abstract
The concerted function of the large number of ion channels expressed in excitable cells, including brain neurons, shapes diverse signaling events by controlling the electrical properties of membranes. It has long been recognized that specific groups of ion channels are functionally coupled in mediating ionic fluxes that impact membrane potential, and that these changes in membrane potential impact ion channel gating. Recent studies have identified distinct sets of ion channels that can also physically and functionally associate to regulate the function of either ion channel partner beyond that afforded by changes in membrane potential alone. Here, we review canonical examples of such ion channel partnerships, in which a Ca2+ channel is partnered with a Ca2+-activated K+ channel to provide a dedicated route for efficient coupling of Ca2+ influx to K+ channel activation. We also highlight examples of non-canonical ion channel partnerships between Ca2+ channels and voltage-gated K+ channels that are not intrinsically Ca2+ sensitive, but whose partnership nonetheless yields enhanced regulation of one or the other ion channel partner. We also discuss how these ion channel partnerships can be shaped by the subcellular compartments in which they are found and provide perspectives on how recent advances in techniques to identify proteins in close proximity to one another in native cells may lead to an expanded knowledge of other ion channel partnerships.
Highlights
Neuronal voltage-gated ion channels interact with a constellation of proteins that impact their activity, subcellular localization, and associated signaling pathways
Neuronal Ca2+ signals initiated by Ca2+ influx through plasma membrane (PM) VGCCs can be accompanied by endoplasmic reticulum (ER) Ca2+ release, amplifying the Ca2+ signal beyond that produced by opening of the PM Ca2+ channel alone
Members of the small-conductance Ca action potential stimulus-dependent trigger for CICR leading to activation of KCa channels, expressed in brain neurons where they are important for regulation intrinsic excitability which contribute to repolarizing the membrane potential to affect subsequent action potential firing
Summary
Neuronal voltage-gated ion channels interact with a constellation of proteins that impact their activity, subcellular localization, and associated signaling pathways. Diversity in the gating properties and physiological roles of many voltage-gated ion channels is generated by interactions of the channel’s pore-forming α subunits with auxiliary subunits that control channel activity and membrane trafficking. The interaction of VGCCs with the synaptic vesicle exocytosis machinery in axon terminals is a prominent and well-explored example of an ion channel–protein partnership that is crucial to brain function [20]. In addition to these interactions, the partnership of VGCCs with numerous other ion channels provides a key mechanism to functionally organize VGCC-dependent
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