Voltage- and calcium-dependent inactivation in high voltage-gated Ca2+ channels

 Calcium influx into cardiac myocytes via voltage-gated Ca channels is a key step in initiating the contractile response. During prolonged depolarizations, toxic Ca2+ overload is prevented by channel inactivation occurring through two different processes identified by their primary trigger: voltage or intracellular Ca2+. In physiological situations, cardiac L-type (CaV1.2) Ca2+ channels inactivate primarily via Ca2+-dependent inactivation (CDI), while neuronal P/Q (CaV2.1) Ca2+ channels use preferentially voltage-dependent inactivation (VDI). In certain situations however, these two types of channels have been shown to be able to inactivate by both processes.From a structural view point, the rearrangement occurring during CDI and VDI is not precisely known, but functional studies have underlined the role played by at least 2 channel sequences: a C-terminal binding site for the Ca2+ sensor calmodulin, essential for CDI, and the loop connecting domains I and II, essential for VDI. The conserved regulation of VDI and CDI by the auxiliary channel ββ subunit strongly suggests that these two mechanisms may use a set of common protein–protein interactions that are influenced by the auxiliary subunit. We will review our current knowledge of these interactions. New data are presented on L-P/Q (CaV1.2/CaV2.1) channel chimera that confirm the role of the I–II loop in VDI and CDI, and reveal some of the essential steps in Ca2+ channel inactivation.