Molecular determinants of inactivation in voltage‐gated Ca²⁺ channels

Abstract

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 (Cav2.1) 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 α1‐subunits and by interactions with other channel subunits. This review focuses on structural determinants of Ca2+ channel inactivation in different parts of Ca2+ channel α1‐subunits, including pore‐forming transmembrane segments and loops, intracellular domain linkers and the carboxyl terminus. Inactivation is also affected by the interaction of the α1‐subunits with auxiliary β‐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.

Molecular Modeling of Interactions of Dihydropyridines and Phenylalkylamines with the Inner Pore of the L-Type Ca2+Channel

“…showed that alanine substitution for the residues corresponding to Ile-1470 and Ile-1471 at the crossover slowed the onset of inactivation. In addition, substitution of some of the hydrophobic residues closer to the C-end of IIIS6 can dramatically decrease the rate of inactivation (IF1612/ 1613AA in IIIS6 of Ca v 2.1; Hering et al, 2000;Sokolov et al, 2000). Both observations are consistent with our proposal that DHP antagonists could interact with a closed state that resembles the inactivated state and stabilize it by interaction at the level of the IIIS6 and IVS6 helical crossover.…”

Increase in Expression of α1 and α2/δ1 Subunits of L-Type High Voltage-Gated Calcium Channels After Sustained Ethanol Exposure in Cerebral Cortical Neurons

“…Among these subunits, α1 subunits form a pore through which Ca 2+ passes and other subunits play roles to modulate α1 subunit functions (8,12,13). However, there are few available data on the mechanisms of functional increase in L-type HVCCs, that is, which Ltype HVCC subunits are involved in the up-regulation of the HVCCs after chronic exposure to ethanol.…”

Clusters of non-truncating mutations of P/Q type Ca2+ channel subunit Cav2.1 causing episodic ataxia 2

“…30 They do not affect, either, the residues involved in channel inactivation (not shown in fig 2) in the S5-S6 repeat I 31 or the S6 repeat III. 32 Three mutations are located outside these preferential regions. The first one (DY1594;A1593D) in IV-S1 is associated with a very mild episodic phenotype without permanent signs.…”