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Papers In Press, published online ahead of print September 19, 2000
Department of Physiology and Pharmacology, Sackler School of Medicine, Tel Aviv 69978
Corresponding Author: dascaln{at}post.tau.ac.il
Neuronal voltage-dependent Ca2+ channels (VDCCs) of the N (
J. Biol. Chem, 10.1074/jbc.M005881200
Submitted on July 5, 2000
Accepted on September 19, 2000
Modulation of L-type Ca2+ channels by G{beta
} and calmodulin via interactions with N- and C-termini of alpha1C
1B) and P/Q (
1A) type are inhibited by neurotransmitters that activate Gi/o G proteins; a major part of the inhibition is voltage-dependent, relieved by depolarization, and results from a direct binding of G{beta
} subunit of G proteins to the channel. Since cardiac and neuronal L-type (
1C) VDCCs are not modulated in this way, they are presumed to lack interaction with G{beta
}. However, here we demonstrate that both G{beta
} and calmodulin directly bind to cytosolic N and C termini of the
1C subunit. Coexpression of G{beta
} reduces the current via the L-type channels. The inhibition depends on the presence of calmodulin, occurs at basal cellular levels of Ca2+, and is eliminated by EGTA. The N- and C-termini of
1C appear to serve as partially independent but interacting inhibitory gates. Deletion of the N-terminus or of the distal half of the C-terminus eliminates the inhibitory effect of G{beta
}. Deletion of the N-terminus (which binds calmodulin) profoundly impairs the Ca2+/calmodulin - dependent inactivation. We propose that G{beta
} and calmodulin regulate the L-type Ca2+ channel in a concerted manner via a molecular inhibitory scaffold formed by N- and C-termini of
1C.
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