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Chemically Distinct Ligands Promote Differential CB₁ Cannabinoid Receptor-Gi Protein Interactions

Neuroscience of Drug Abuse Research Program, J. L. Chambers Biomedical/Biotechnology Research Institute, North Carolina Central University, Durham, North Carolina

To understand how structurally distinct ligands regulate CB₁ receptor interactions with Gi1, Gi2, and Gi3, we quantified the Gi and proteins that coimmunoprecipitate with the CB₁ receptor from a detergent extract of N18TG2 membranes in the presence of ligands. A mixture of A, R, G_GDP (or G_), and ARG_GDP (or ARG_) complexes was observed in the presence of aminoalkylindole (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone (WIN 55,212-2) for all three RGi complexes, cannabinoid desacetyllevonantradol for Gi1 and Gi2, and eicosanoid (R)-methanandamide for Gi3. Desacetyllevonantradol maintained RGi3 complexes and (R)-methanandamide maintained RGi1 and RGi2 complexes even in the presence of a nonhydrolyzable GTP analog. The biaryl pyrazole antagonist N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboximide hydrochloride (SR141716) maintained all three RGi complexes. G proteins, and to a certain extent G2, exhibited the same association/dissociation pattern as the G proteins. A GDP analog had no influence on any of these association/dissociation reactions and failed to promote sequestration of G proteins. These results can be explained by invoking the existence of an inverse agonist-supported inactive state in the ternary complex equilibrium model. WIN 55,212-2 behaves as an agonist for all three Gi subtypes; SR141716 behaves as an inverse agonist for all three Gi subtypes; desacetyllevonantradol behaves as an agonist for Gi1 and Gi2, and an inverse agonist at Gi3; and (R)-methanandamide behaves as an inverse agonist at Gi1 and Gi2, and an agonist at Gi3. These ligand-selective G protein responses imply that multiple conformations of the receptor could be evoked by ligands to regulate individual G proteins.

Address correspondence to: Dr. Somnath Mukhopadhyay, Neuroscience of Drug Abuse Research Program, J. L. Chambers Biomedical/Biotechnology Research Institute, North Carolina Central University, 700 George Street, Durham, NC 27707. E-mail: smukhopadhyay{at}nccu.edu

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