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Originally published In Press as doi:10.1074/jbc.M306645200 on September 24, 2003

J. Biol. Chem., Vol. 278, Issue 49, 49386-49400, December 5, 2003
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Competitive and Synergistic Interactions of G Protein {beta}2 and Ca2+ Channel {beta}1b Subunits with Cav2.1 Channels, Revealed by Mammalian Two-hybrid and Fluorescence Resonance Energy Transfer Measurements*

Alexander Hümmer, Oliver Delzeith, Shannon R. Gomez, Rosa L. Moreno, Melanie D. Mark, and Stefan Herlitze{ddagger}

From the Department of Neurosciences, Case Western Reserve University, School of Medicine, Cleveland, Ohio 44106-4975

Presynaptic Ca2+ channels are inhibited by metabotropic receptors. A possible mechanism for this inhibition is that G protein {beta}{gamma} subunits modulate the binding of the Ca2+ channel {beta} subunit on the Ca2+ channel complex and induce a conformational state from which channel opening is more reluctant. To test this hypothesis, we analyzed the binding of Ca2+ channel {beta} and G protein {beta} subunits on the two separate binding sites, i.e. the loopI–II and the C terminus, and on the full-length P/Q-type {alpha}12.1 subunit by using a modified mammalian two-hybrid system and fluorescence resonance energy transfer (FRET) measurements. Analysis of the interactions on the isolated bindings sites revealed that the Ca2+ channel {beta}1b subunit induces a strong fluorescent signal when interacting with the loopI–II but not with the C terminus. In contrast, the G protein {beta} subunit induces FRET signals on both the C terminus and loopI–II. Analysis of the interactions on the full-length channel indicates that Ca2+ channel {beta}1b and G protein {beta} subunits bind to the {alpha}1 subunit at the same time. Coexpression of the G protein increases the FRET signal between {alpha}1/{beta}1b FRET pairs but not for {alpha}1/{beta}1b FRET pairs where the C terminus was deleted from the {alpha}1 subunit. The results suggest that the G protein alters the orientation and/or association between the Ca2+ channel {beta} and {alpha}12.1 subunits, which involves the C terminus of the {alpha}1 subunit and may corresponds to a new conformational state of the channel.


Received for publication, June 23, 2003 , and in revised form, September 22, 2003.

* This work was supported by National Institutes of Health Grant R01 NS42623-01A1 (to S. H.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains 2 tables.

{ddagger} To whom correspondence should be addressed: Dept. of Neurosciences, Case Western Reserve University, School of Medicine, Rm. E604, 10900 Euclid Ave., Cleveland, OH 44106-4975. Tel.: 216-368-1804; Fax: 216-368-4650; E-mail: sxh106{at}pop.cwru.edu.


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