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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
(CaV2.1) 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; CaV2.1; subunit; inactivation mechanism; palmitoylation; membrane anchoring; I-II loop
Copyright © 2000 Society for Neuroscience 0270-6474/00/20249046-07$05.00/0
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