Molecular endpoints of Ca/calmodulin- and voltage-dependent inactivation of Cav1.3 channels

Ca entry through high voltage–gated Ca (CaV1 and CaV2) channels selectively triggers numerous neurobiological processes, including transmitter release, gene transcription, and memory formation (Berridge et al., 2000). Fitting with these vital roles, CaV1/2 channels are highly regulated through a variety of feedback mechanisms that inactivate channels in response to either intracellular Ca elevations (e.g., Ca-dependent inactivation [CDI]) or voltage-dependent conformational changes (e.g., voltage-dependent inactivation [VDI]). The initial steps involved in these prototypic forms of regulation have been studied extensively. For example, it is known that Ca binds to a constitutively associated calmodulin (CaM), which then interacts with other sites on the channel to induce CDI (Lee et al., 1999, 2003; Peterson et al., 1999; Zühlke et al., 1999; Erickson et al., 2001, 2003; Pitt et al., 2001; Mori et al., 2004; Dick et al., 2008; Tadross et al., 2008). Similarly, it is well accepted that voltage-dependent conformational changes of CaV1/2 channels are initially triggered by movement of four homologous voltage-sensing domains, each consisting of transmembrane helices S1–S4 (Swartz, 2008). These rearrangements open the intracellular gate, comprised of distal S6 segments (Liu et al., 1997; Xie et al., 2005),