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The Journal of Neuroscience, December 15, 2000, 20(24):9046-9052

The _2a Subunit Is a Molecular Groom for the Ca²⁺ Channel Inactivation Gate

S. Restituito¹, T. Cens¹, C. Barrere¹, S. Geib², S. Galas¹, M. De Waard², and P. Charnet¹

¹ Centre de Recherches de Biochimie Macromoléculaire, Centre National de la Recherche Scientifique, Unité Propre de Recherche 1086, Institut Fédératif de Recherche 24, 34293 Montpellier Cedex 05, France, and ² Institut National de la Santé et de la Recherche Médicale U464, Institut Fédératif Jean Roche, Laboratoire de Neurobiologie des Canaux Ioniques, 13916 Marseille Cedex 20, France

Ca²⁺ channel inactivation is a key element in controlling the level of Ca²⁺ entry through voltage-gated Ca²⁺ channels. Interaction between the pore-forming ₁ subunit and the auxiliary  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 _2a subunit strongly reduces _1A (Ca_V2.1) Ca²⁺ channel inactivation. This effect can be mimicked by the addition of a transmembrane segment to the N terminus of the _2a subunit. Inhibition of inactivation by _2a also requires a link between MAS and another important molecular determinant, the  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 _2a subunit, in which the immobilization of the channel inactivation gate occurs by means of MAS and BID.

Key words: P/Q type Ca²⁺ channels; Ca_V2.1; subunit; inactivation mechanism; palmitoylation; membrane anchoring; I-II loop

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Copyright © 2000 Society for Neuroscience  0270-6474/00/20249046-07$05.00/0

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