Molecular determinants of inactivation in voltage-gated Ca super(2+) channels

Evolution has created a large family of different classes of voltage-gated Ca super(2+) channels and a variety of additional splice variants with different inactivation properties. Inactivation controls the amount of Ca super(2+) entry during an action potential and is, therefore, believed to play an important role in tissue-specific Ca super(2+) signalling. Furthermore, mutations in a neuronal Ca super(2+) channel (Ca sub(v)2.1) 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. Ca super(2+) 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 Ca super(2+)-dependent inactivation mechanism. Inactivation kinetics of Ca super(2+) channels are determined by the intrinsic properties of their pore-forming alpha sub(1)-subunits and by interactions with other channel subunits. This review focuses on structural determinants of Ca super(2+) channel inactivation in different parts of Ca super(2+) channel alpha sub(1)-subunits, including poreforming transmembrane segments and loops, intracellular domain linkers and the carboxyl terminus. Inactivation is also affected by the interaction of the alpha sub(1)-subunits with auxiliary beta -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 Ca super(2+) channel inactivation. Structural concepts of Ca super(2+) channel inactivation are discussed.