Résumé
Ca2+ channel inactivation is a key element in controlling the level of Ca2+ entry through voltage-gated Ca2+ channels. Interaction between the pore-forming alpha (1) subunit and the auxiliary beta subunit is known to be a strong modulator of voltage-dependent inactivation. Here, we demonstrate that an N-terminal membrane anchoring site (MAS) of the beta (2a) subunit strongly reduces alpha (1A) (Ca(V)2.1) Ca2+ channel inactivation. This effect can be mimicked by the addition of a transmembrane segment to the N terminus of the beta (2a) subunit. Inhibition of inactivation by beta (2a) also requires a link between MAS and another important molecular determinant, the beta interaction domain (BID). Our data suggest that mobility of the Ca2+ channel I-II loop is necessary for channel inactivation. Interaction of this loop with other identified intracellular channel domains may constitute the basis of voltage-dependent inactivation. We thus propose a conceptually novel mechanism for slowing of inactivation by the beta (2a) subunit, in which the immobilization of the channel inactivation gate occurs by means of MAS and BID.