Ion Channel Partnerships: Odd and Not-So-Odd Couples Controlling Neuronal Ion Channel Function

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.