title: The [beta]2a subunit is a molecular groom for the Ca2+ channel inactivation gate.
abstract: Ca(2+) channel inactivation is a key element in controlling the level of Ca(2+) entry through voltage-gated Ca(2+) 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) Ca(2+) 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 Ca(2+) 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.
authors: 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.
authors: S
authors: S
authors: Restituito
authors: T
authors: T
authors: Cens
authors: C
authors: C
authors: Barrere
authors: S
authors: S
authors: Geib
authors: S
authors: S
authors: Galas
authors: M
authors: M
authors: De Waard
authors: P
authors: P
authors: Charnet
mesh_terms: D000818:Animals; D001464:Barium / Q000494:pharmacology; D001665:Binding Sites / Q000235:genetics; D015220:Calcium Channels / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D020865:Calcium Channels, P-Type / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D020907:Calcium Channels, Q-Type / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D002614:Chelating Agents / Q000494:pharmacology; D004594:Electrophysiology; D005455:Fluorescent Antibody Technique; D005982:Glutathione Transferase / Q000235:genetics; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects / Q000502:physiology*; D016297:Mutagenesis, Site-Directed; D009865:Oocytes / Q000166:cytology / Q000378:metabolism; D018408:Patch-Clamp Techniques; D017434:Protein Structure, Tertiary / Q000235:genetics; D021122:Protein Subunits; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship; D014162:Transfection; D014981:Xenopus
chemical_list: D015220:Calcium Channels; D020865:Calcium Channels, P-Type; D020907:Calcium Channels, Q-Type; D002614:Chelating Agents; D021122:Protein Subunits; D011993:Recombinant Fusion Proteins; D001464:Barium; D005982:Glutathione Transferase