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Vol. 286, Issue 1, 345-353, July 1998
UNC Neuroscience Center (M.M.L., V.J.W., C.P.L., R.B.M.),
Departments of
Pharmacology (V.J.W., R.B.M.) and
Psychiatry (C.P.L.,
R.B.M.),
Curricula in Neurobiology (M.M.L., R.B.M.) and
Toxicology
(C.P.L., R.B.M.), University of North Carolina School of Medicine,
Chapel Hill, North Carolina and
Department of Medicinal Chemistry and
Molecular Pharmacology (D.E.N.), School of Pharmacy and Pharmacal
Sciences, Purdue University, West Lafayette, Indiana
The role of drug efficacy in agonist-induced desensitization was
studied in C-6 glioma cells transfected with the monkey dopamine D1A (mD1A) receptor. Dopamine pretreatment for
2 hr produced greater than 80% loss of responsiveness in the
stimulation of cAMP accumulation that was blocked by the D1
antagonist SCH23390. A series of full and partial D1
agonists from structurally dissimilar classes were then examined. Three
full agonists (dihydrexidine, SKF82958, A77636) desensitized the
receptor to the same extent as dopamine, whereas two other full
agonists (dinapsoline and A68930) and all the partial agonists tested
(SKF38393, pergolide and d-lysergic acid diethylamide tartrate)
produced only partial desensitization (i.e., 50% that of dopamine). Whereas partial agonists (i.e., SKF38393,
pergolide and d-lysergic acid diethylamide tartrate) caused no
alteration in ligand-accessible mD1A receptors, four of the
full agonists (dopamine, dihydrexidine, dinapsoline, A68930) caused a
30 to 40% reduction in receptor number. One full agonist, A77636,
caused nearly an 80% decrease in receptor number, despite the fact
that the degree of functional desensitization was similar to the other full agonists. The desensitization of the D1 receptor was
homologous, not affecting beta-2 adrenergic receptors
endogenous to C-6 cells. Neither incubation with cAMP analogs, nor
inhibition of protein kinase A, affected dopamine-induced
desensitization, suggesting a cAMP-independent mechanism in this cell
line. Together, these data suggest that functional desensitization of
the mD1A receptor expressed in C-6 glioma cells is a
cAMP-independent mechanism, cannot be predicted reliably from agonist
efficacy for stimulating adenylate cyclase and can occur in the absence
of changes in receptor number.
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