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Molecular determinants of inactivation in voltage-gated Ca²⁺ channels

Steffen Hering, Stanislav Berjukow, Stanislav Sokolov, Rainer Marksteiner, Regina G. Weiß, Richard Kraus and Evgeni N. Timin*

1. Evolution has created a large family of different classes of voltage-gated Ca²⁺ channels and a variety of additional splice variants with different inactivation properties. Inactivation controls the amount of Ca²⁺ entry during an action potential and is, therefore, believed to play an important role in tissue-specific Ca²⁺ signalling. Furthermore, mutations in a neuronal Ca²⁺ channel (Ca_v2.1) that are associated with the aetiology of neurological disorders such as familial hemiplegic migraine and ataxia cause significant changes in the process of channel inactivation. Ca²⁺ channels of a given subtype may inactivate by three different conformational changes: a fast and a slow voltage-dependent inactivation process and in some channel types by an additional Ca²⁺-dependent inactivation mechanism. Inactivation kinetics of Ca²⁺ channels are determined by the intrinsic properties of their pore-forming ₁-subunits and by interactions with other channel subunits. This review focuses on structural determinants of Ca²⁺ channel inactivation in different parts of Ca²⁺ channel ₁-subunits, including pore-forming transmembrane segments and loops, intracellular domain linkers and the carboxyl terminus. Inactivation is also affected by the interaction of the ₁-subunits with auxiliary -subunits and intracellular regulator proteins. The evidence shows that pore-forming S6 segments and conformational changes in extra- (pore loop) and intracellular linkers connected to pore-forming segments may play a principal role in the modulation of Ca²⁺ channel inactivation. Structural concepts of Ca²⁺ channel inactivation are discussed.

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