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

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 GTPγS (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.

• Publication year

  2000

• Venue

  Journal of Biological Chemistry

• Publication date

  2000-10-20

• Fields of study

  Biology, Medicine, Chemistry

• Identifiers
  DOI 10.1074/jbc.M002780200PMID 10926927
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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