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Vol. 57, Issue 4, 820-825, April 2000
Department of Neurobiology, The Weizmann Institute of Science,
Rehovot, Israel (M.L.B., I.N., T.A.-R., R.L., Z.V.), and Metabolic
Diseases Branch, National Institute of Diabetes and Digestive and
Kidney Diseases, National Institutes of Health, Bethesda, Maryland
(W.F.S.)
Prolonged Gi/o protein-coupled receptor activation has been
shown to lead to receptor internalization and receptor desensitization. In addition, it is well established that although acute activation of
these receptors leads to inhibition of adenylyl cyclase (AC), long-term
activation results in increased AC activity (especially evident on
removal of the inhibitory agonist), a phenomenon defined as AC
superactivation or sensitization. Herein, we show that chronic exposure
to agonists of Gi-coupled receptors also leads to a
decrease in cholate detergent solubility of G protein subunits, and
that antagonist treatment after such chronic agonist exposure leads to
a time-dependent reversal of the cholate insolubility. With Chinese
hamster ovary and COS cells transfected with several
Gi/o-coupled receptors (i.e., µ- and 
-opioid, and
m4-muscarinic), we observed that although no overall change
occurred in total content of G
i- and
1-subunits, chronic agonist treatment led to a marked
reduction in the ability of 1% cholate to solubilize
G
as well as Gi. This solubility shift
is exclusively observed with Gi, and was not seen with
Gs. The disappearance and reappearance of
Gi and G subunits from and to the detergent-soluble fractions occur with similar time courses as observed
for the onset and disappearance of AC superactivation. Lastly,
pertussis toxin, which blocks acute and chronic agonist-induced AC
inhibition and superactivation, also blocks the shift in detergent solubility. These results suggest a correlation between the solubility shift of the heterotrimeric Gi protein and the generation
of AC superactivation.
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