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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-Cardona{ddagger}, Oliver Kudlacek{ddagger}, Qiong Yang{ddagger}, Horst Ahorn§, Michael Freissmuth{ddagger}, , and Christian Nanoff{ddagger}

From the {ddagger}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

ABSTRACT Back to Top

Abstract: 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 Gαi1 by D2N, and D2receptor-promoted GTP{gamma}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.

Received for publication April 3, 2000. Revision received July 5, 2000.

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