11359870

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Heterozygous CB1 receptor knockout mice were used to examine the effect of reduced CB1 receptor density on G-protein activation in membranes prepared from four brain regions: cerebellum, hippocampus, striatum/globus pallidus (striatum/GP) and cingulate cortex. Results showed that CB1 receptor levels were approximately 50% lower in heterozygous mice in all regions examined. However, maximal stimulation of [(35)S]guanosine-5'-(gamma-O-thio) triphosphate ([(35)S]GTPgammaS) binding by the high efficacy agonist WIN 55,212-2 was reduced by only 20-25% in most brain regions, with the exception of striatum/GP where the decrease in stimulation was as predicted (approximately 50%). Furthermore, although the efficacies of the cannabinoid partial agonists, methanandamide and (9)-tetrahydrocannabinol, were similarly lower in heterozygous mice, their relative efficacies compared with WIN 55,212-2 were generally unchanged. Saturation analysis of net WIN 55,212-2-stimulated [(35)S]GTPgammaS binding showed that decreased stimulation by WIN 55,212-2 in striatum/GP of heterozygous mice was caused by a decrease in the apparent affinity of net-stimulated [(35)S]GTPgammaS binding. The apparent maximal number of binding sites (B(max)) values of net WIN 55,212-2-stimulated [(35)S]GTPgammaS binding were unchanged in cerebellum and striatum/GP of heterozygous mice, but decreased in cingulate cortex, with a similar trend in hippocampus. Moreover, in every region except cingulate cortex, the maximal number of net-stimulated [(35)S]GTPgammaS binding sites per receptor was significantly increased in heterozygous mice. These results indicate region-dependent increases in the apparent efficiency of CB1 receptor-mediated G-protein activation in heterozygous CB1 knockout mice.

eng

IM

MEDLINE

0022-3042

Print

NLM

1048-57

pubmed-meshheading:11359870-Animals, pubmed-meshheading:11359870-Arachidonic Acids, pubmed-meshheading:11359870-Benzoxazines, pubmed-meshheading:11359870-Binding Sites, pubmed-meshheading:11359870-Brain, pubmed-meshheading:11359870-Cannabinoids, pubmed-meshheading:11359870-Cell Membrane, pubmed-meshheading:11359870-Cerebellum, pubmed-meshheading:11359870-Corpus Striatum, pubmed-meshheading:11359870-Crosses, Genetic, pubmed-meshheading:11359870-Female, pubmed-meshheading:11359870-GTP-Binding Proteins, pubmed-meshheading:11359870-Globus Pallidus, pubmed-meshheading:11359870-Guanosine 5'-O-(3-Thiotriphosphate), pubmed-meshheading:11359870-Gyrus Cinguli, pubmed-meshheading:11359870-Heterozygote, pubmed-meshheading:11359870-Hippocampus, pubmed-meshheading:11359870-Kinetics, pubmed-meshheading:11359870-Mice, pubmed-meshheading:11359870-Mice, Inbred C57BL, pubmed-meshheading:11359870-Mice, Knockout, pubmed-meshheading:11359870-Morpholines, pubmed-meshheading:11359870-Naphthalenes, pubmed-meshheading:11359870-Organ Specificity, pubmed-meshheading:11359870-Receptors, Cannabinoid, pubmed-meshheading:11359870-Receptors, Drug, pubmed-meshheading:11359870-Tetrahydrocannabinol

Agonist efficacy and receptor efficiency in heterozygous CB1 knockout mice: relationship of reduced CB1 receptor density to G-protein activation.

Journal Article, Research Support, U.S. Gov't, P.H.S.