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J Biol Chem, Vol. 274, Issue 31, 22081-22088, July 30, 1999

Calmodulin Binding to G Protein-coupling Domain of Opioid Receptors

From the Departments of Biopharmaceutical Sciences and Pharmaceutical Chemistry and the Center for the Neurobiology of Drug Addiction, University of California San Francisco, San Francisco, California 94143-0446

The ubiquitous intracellular Ca²⁺ sensor calmodulin (CaM) regulates numerous proteins involved in cellular signaling of G protein-coupled receptors, but most known interactions between GPCRs and CaM occur downstream of the receptor. Using a sequence-based motif search, we have identified the third intracellular loop of the opioid receptor family as a possible direct contact point for interaction with CaM, in addition to its established role in G protein activation. Peptides derived from the third intracellular loop of the µ-opioid (OP₃) receptor strongly bound CaM and were able to reduce binding interactions observed between CaM and immunopurified OP₃ receptor. Functionally, CaM reduced basal and agonist-stimulated ³⁵S-labeled guanosine 5'-3-O-(thio)triphosphate incorporation, a measure of G protein activation, in membranes containing recombinant OP₃ receptor. Changes in CaM membrane levels as a result of overexpression or antisense CaM suppression inversely affected basal and agonist-induced G protein activation. The ability of CaM to abolish high affinity binding sites of an agonist at OP₃ further supports the hypothesis of a direct interaction between CaM and opioid receptors. An OP₃ receptor mutant with a Lys²⁷³  Ala substitution (K273A-OP₃), an amino acid predicted to play a critical role in CaM binding based on motif structure, was found to be unaffected by changes in CaM levels but coupled more efficiently to G proteins than the wild-type receptor. Stimulation of both the OP₁ (-opioid) and OP₃ wild-type receptors, but not the K273A-OP₃ mutant, induced release of CaM from the plasma membrane. These results suggest that CaM directly competes with G proteins for binding to opioid receptors and that CaM may itself serve as an independent second messenger molecule that is released upon receptor stimulation.

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