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Vol. 57, Issue 5, 1000-1010, May 2000
-Subunits with Different
Potencies
Department of Pharmacology and Toxicology, University of Arkansas
for Medical Sciences, Little Rock, Arkansas (P.L.P, N.A.M.); and
Department of Physiology and Pharmacology, and Center for Investigative
Neuroscience, Bowman Gray School of Medicine, Wake Forest
University, Winston-Salem, North Carolina (C.S.B., S.R.C.)
Previous studies had shown that the amplification factors for
cannabinoid receptors, defined as the number of total G proteins activated per occupied receptor, differs between several rat brain regions. In this study, we sought to determine which specific Gi/Go
subunits were activated by CB1 receptors in
several rat brain regions and if this coupling might explain the
regional differences in receptor/G protein amplification factors.
Furthermore, we examined whether cannabinoid agonists might activate
different subtypes of G subunits with varying degrees of
efficacy and/or potency. Activation of specific G proteins by
cannabinoid receptors was evaluated by the ability of the agonist WIN
55212-2 to stimulate incorporation of
[
-32P]azidoanilido-GTP into G subunits
in membranes. Photolabeled G proteins were either directly resolved
using urea/SDS-polyacrylamide gel electrophoresis or first
immunoprecipitated with specific antisera for different
G subunits before electrophoresis. Individual
G subunits were separated into distinct bands on a
single gel and the amount of agonist-induced increase in radioactivity
was quantified by densitometry. Stimulation of CB1 receptors by WIN
55212-2 resulted in the activation of a distinct pattern of at least
five different Gi/Go subunits in several
brain regions. Furthermore, although the pattern of G proteins
activated by WIN 55212-2 appeared to be similar across brain regions,
slight differences were observed in both the percentage of increase and
the amount of the individual G subunits activated. Most
importantly, the amount of WIN 55212-2 required to half-maximally activate individual G proteins in the cerebellum varied over a 30-fold
range for different G subunits. These results suggest that cannabinoid receptors activate multiple G proteins simultaneously in several brain regions and both the efficacy and potency of cannabinoid agonists to activate individual G subunits
may vary considerably.
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