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Vol. 57, Issue 1, 162-170, January 2000

The CB1 Cannabinoid Receptor Juxtamembrane C-Terminal Peptide Confers Activation to Specific G proteins in Brain

Somnath Mukhopadhyay, Helen H. McIntosh, Devin B. Houston,1 and Allyn C. Howlett

Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine, St. Louis, Missouri

Under reducing conditions of SDS-polyacrylamide gel electrophoresis, the CB1 receptor exists in its monomeric form as well as in an SDS-resistant high molecular weight form that appears to be devoid of G proteins. The CB1 cannabinoid receptor was immunoprecipitated from 3-[(3-cholamidopropyl)dimethylammonio]propanesulfonate-solubilized rat brain membranes using an antibody against the CB1 receptor N terminus. The CB1 receptor was coimmunoprecipitated with its associated G proteins, specifically those of the Galpha i/o family, but not Galpha s, Galpha q, or Galpha z. The CB1 receptor-Galpha i/o complex existed in the absence of exogenous agonists, and the cannabinoid receptor agonist desacetyllevonantradol failed to alter the stoichiometry of the receptor-Galpha i/o interaction. Guanosine-5'-O-(3-thio)triphosphate could disrupt the interaction. A peptide derived from the CB1 receptor juxtamembrane C-terminal domain, peptide CB1401-417, autonomously activates Gi/o proteins. Peptide CB1401-417 competitively disrupted the CB1 receptor association with Galpha o and Galpha i3 but not Galpha i1 or Galpha i2. This G protein specificity was also observed in detergent extracts from membranes of the frontal cortex, striatum, and cerebellum. Alternative peptides, including peptides from the CB1 receptor third intracellular loop and the G protein activating peptide mastoparan-7, failed to promote uncoupling from Galpha o. A CB2 receptor juxtamembrane C-terminal peptide failed to disrupt the CB1 receptor-Galpha o complex. These studies illustrate that the CB1 receptor can exist as an SDS-resistant multimer. In 3-[(3-cholamidopropyl)dimethylammonio]propanesulfonate detergent, the CB1 receptor exists in a complex with G proteins of the Gi/o family in the absence of exogenous agonists. Furthermore, this study provides the first description of domain specificity for interaction with a selective set of G proteins.

1 Present address: National Enzyme Company, Forsyth, MO 65653.

Copyright © 2000 by The American Society for Pharmacology and Experimental Therapeutics


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