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PLoS One. 2013 May 7;8(5):e63262. doi: 10.1371/journal.pone.0063262. Print 2013.

The second intracellular loop of the human cannabinoid CB2 receptor governs G protein coupling in coordination with the carboxyl terminal domain.

Author information

1
Institute of Biochemistry, College of Life Sciences, Zhejiang University, Hangzhou, Zhejiang, China.

Erratum in

  • PLoS One. 2013;8(11). doi:10.1371/annotation/11146424-f236-4fc6-85b2-cd393cfb6a94.

Abstract

The major effects of cannabinoids and endocannabinoids are mediated via two G protein-coupled receptors, CB1 and CB2, elucidation of the mechanism and structural determinants of the CB2 receptor coupling with G proteins will have a significant impact on drug discovery. In the present study, we systematically investigated the role of the intracellular loops in the interaction of the CB2 receptor with G proteins using chimeric receptors alongside the characterization of cAMP accumulation and ERK1/2 phosphorylation. We provided evidence that ICL2 was significantly involved in G protein coupling in coordination with the C-terminal end. Moreover, a single alanine substitution of the Pro-139 in the CB2 receptor that corresponds to Leu-222 in the CB1 receptor resulted in a moderate impairment in the inhibition of cAMP accumulation, whereas mutants P139F, P139M and P139L were able to couple to the Gs protein in a CRE-driven luciferase assay. With the ERK activation experiments, we further found that P139L has the ability to activate ERK through both Gi- and Gs-mediated pathways. Our findings defined an essential role of the second intracellular loop of the CB2 receptor in coordination with the C-terminal tail in G protein coupling and receptor activation.

PMID:
23667597
PMCID:
PMC3646771
DOI:
10.1371/journal.pone.0063262
[Indexed for MEDLINE]
Free PMC Article

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