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J. Biol. Chem. 275 (42): 32672-32680

© 2000 by The American Society for Biochemistry and Molecular Biology, Inc.

Binding of Calmodulin to the D2-Dopamine Receptor Reduces Receptor Signaling by Arresting the G Protein Activation Switch*

Elisa Bofill-CardonaDagger , Oliver KudlacekDagger , Qiong YangDagger , Horst Ahorn§, Michael FreissmuthDagger , and Christian NanoffDagger

From the Dagger  Institute of Pharmacology, University of Vienna, Währinger Strasse 13a, A-1090 Vienna and § Boehringer Ingelheim Austria GmbH, Dr.-Boehringer-Gasse 5, A-1120 Vienna, Austria

Signaling by D2-dopamine receptors in neurons likely proceeds in the presence of Ca2+ oscillations. We describe here the biochemical basis for a cross-talk between intracellular Ca2+ and the D2 receptor. By activation of calmodulin (CaM), Ca2+ directly inhibits the D2 receptor; this conclusion is based on the following observations: (i) The receptor contains a CaM-binding motif in the NH2-terminal end of the third loop, a domain involved in activating Gi/o. A peptide fragment encompassing this domain (D2N) bound dansylated CaM in a Ca2+-dependent manner (KD ~ 0.1 µM). (ii) Activation of purified Galpha i1 by D2N, and D2 receptor-promoted GTPgamma S (guanosine 5'-(3-O-thio)triphosphate) binding in membranes was suppressed by Ca2+/CaM (IC50 ~ 0.1 µM). (iii) If Ca2+ influx was elicited in D2 receptor-expressing HEK293 cells, agonist-dependent inhibition of cAMP formation decreased. This effect was not seen with other Gi-coupled receptors (A1-adenosine and Mel1A-melatonin receptor). (iv) The D2 receptor was retained by immobilized CaM and radiolabeled CaM was co-immunoprecipitated with the receptor. Specifically, inhibition by CaM does not result from uncoupling the D2 receptor from its cognate G protein(s); rather, CaM directly targets the D2 receptor to block the receptor-operated G protein activation switch.

* This work was supported by Austrian Science Foundation Grants P13097 (to M. F.) and P14273 (to C. N.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed. E-mail: christian. nanoff@univie.ac.at.

Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.

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