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J. Biol. Chem., Vol. 275, Issue 42, 32672-32680, October 20, 2000

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

Elisa Bofill-Cardona, Oliver Kudlacek, Qiong Yang, Horst Ahorn^§, Michael Freissmuth, and Christian Nanoff^¶

From the  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 G_i/o. A peptide fragment encompassing this domain (D2N) bound dansylated CaM in a Ca²⁺-dependent manner (K_D ~ 0.1 µM). (ii) Activation of purified G_i1 by D2N, and D₂ receptor-promoted GTPS (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 G_i-coupled receptors (A₁-adenosine and Mel_1A-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.

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