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Agonist efficacy and receptor efficiency in heterozygous CB1 knockout mice: relationship of reduced CB1 receptor density to G‐protein activation
Author(s) -
Selley Dana E.,
Rorrer W. Kirk,
Breivogel Christopher S.,
Zimmer Anne M.,
Zimmer Andreas,
Martin Billy R.,
SimSelley Laura J.
Publication year - 2001
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.2001.00308.x
Subject(s) - striatum , medicine , endocrinology , agonist , chemistry , stimulation , globus pallidus , cannabinoid receptor , gtp' , hippocampus , cannabinoid , knockout mouse , receptor , biology , basal ganglia , biochemistry , central nervous system , enzyme , dopamine
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′‐(γ‐ O ‐thio) triphosphate ([ 35 S]GTPγS) 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 Δ 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]GTPγS 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]GTPγS binding. The apparent maximal number of binding sites ( B max ) values of net WIN 55,212–2‐stimulated [ 35 S]GTPγS 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]GTPγS 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.