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Molecular Pharmacology

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Research ArticleArticle

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

Somnath Mukhopadhyay, Helen H. McIntosh, Devin B. Houston and Allyn C. Howlett
Molecular Pharmacology January 2000, 57 (1) 162-170;
Somnath Mukhopadhyay
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Helen H. McIntosh
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Devin B. Houston
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Allyn C. Howlett
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Abstract

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 CB1receptor N terminus. The CB1 receptor was coimmunoprecipitated with its associated G proteins, specifically those of the Gαi/o family, but not Gαs, Gαq, or Gαz. The CB1receptor-Gαi/o complex existed in the absence of exogenous agonists, and the cannabinoid receptor agonist desacetyllevonantradol failed to alter the stoichiometry of the receptor-Gαi/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 CB1receptor association with Gαo and Gαi3 but not Gαi1 or Gαi2. 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 Gαo. A CB2receptor juxtamembrane C-terminal peptide failed to disrupt the CB1 receptor-Gαo 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.

Footnotes

  • Send reprint requests to: Dr. Allyn C. Howlett, Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine, 1402 South Grand Blvd., St. Louis, MO 63104. E-mail: howletta{at}slu.edu

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

  • This work was supported in part by NIDA Grants R01-DA03690 and K05-DA00182.

  • Abbreviations:
    MAPK
    mitogen-activated protein kinase
    CAPS
    3-[cyclohexylamino]-1-propanesulfonic acid
    CHAPS
    3-[(3-cholamidopropyl)dimethylammonio]propanesulfonate
    DALN
    desacetyllevonantradol
    ECL
    enhanced chemiluminescence
    GTPγS
    guanosine-5′-O-(3-thio)- triphosphate
    PAGE
    polyacrylamide gel electrophoresis
    • Received June 4, 1999.
    • Accepted October 8, 1999.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 57 (1)
Molecular Pharmacology
Vol. 57, Issue 1
1 Jan 2000
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Research ArticleArticle

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

Somnath Mukhopadhyay, Helen H. McIntosh, Devin B. Houston and Allyn C. Howlett
Molecular Pharmacology January 1, 2000, 57 (1) 162-170;

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Research ArticleArticle

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

Somnath Mukhopadhyay, Helen H. McIntosh, Devin B. Houston and Allyn C. Howlett
Molecular Pharmacology January 1, 2000, 57 (1) 162-170;
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