Ca2 +-dependent modulation of voltage-gated Ca2 + channels

BackgroundVoltage-gated (Cav) Ca2 + channels are multi-subunit complexes that play diverse roles in a wide variety of tissues. A fundamental mechanism controlling Cav channel function involves the Ca2 + ions that permeate the channel pore. Ca2 + influx through Cav channels mediates feedback regulation to the channel that is both negative (Ca2 +-dependent inactivation, CDI) and positive (Ca2 +-dependent facilitation, CDF).Scope of reviewThis review highlights general mechanisms of CDI and CDF with an emphasis on how these processes have been studied electrophysiologically in native and heterologous expression systems.Major conclusionsElectrophysiological analyses have led to detailed insights into the mechanisms and prevalence of CDI and CDF as Cav channel regulatory mechanisms. All Cav channel family members undergo some form of Ca2 +-dependent feedback that relies on CaM or a related Ca2 + binding protein. Tremendous progress has been made in characterizing the role of CaM in CDI and CDF. Yet, what contributes to the heterogeneity of CDI/CDF in various cell-types and how Ca2 +-dependent regulation of Cav channels controls Ca2 + signaling remain largely unexplored.General significanceCa2 + influx through Cav channels regulates diverse physiological events including excitation–contraction coupling in muscle, neurotransmitter and hormone release, and Ca2 +-dependent gene transcription. Therefore, the mechanisms that regulate channels, such as CDI and CDF, can have a large impact on the signaling potential of excitable cells in various physiological contexts. This article is part of a Special Issue entitled Biochemical, biophysical and genetic approaches to intracellular calcium signaling.

► Electrophysiological analysis have revealed detailed mechanisms of Cav channel modulation.
► Cav channels undergo CDI/CDF that relies on Ca2+ binding proteins like calmodulin.
► The heterogeneity of CDI/CDF in various cell-types remains largely unexplored.