HOMOLOGOUS DESENSITIZATION OF THE D-1A DOPAMINE-RECEPTOR - EFFICACY IN CAUSING DESENSITIZATION DISSOCIATES FROM BOTH RECEPTOR OCCUPANCY ANDFUNCTIONAL POTENCY

The role of drug efficacy in agonist-induced desensitization was studi ed in C-6 glioma cells transfected with the monkey dopamine D-1A (mD(1 A)) receptor. Dopamine pretreatment for 2 hr produced greater than 80% loss of responsiveness in the stimulation of cAMP accumulation that w as blocked by the D-1 antagonist SCH23390. A series of full and partia l D-1 agonists from structurally dissimilar classes were then examined . Three full agonists (dihydrexidine, SKF82958, A77636) desensitized t he receptor to the same extent as dopamine, whereas two other full ago nists (dinapsoline and A68930) and all the partial agonists tested (SK F38393, pergolide and d-lysergic acid diethylamide tartrate) produced only partial desensitization (i.e., 50% that of dopamine). Whereas par tial agonists (i.e., SKF38393, pergolide and d-lysergic acid diethylam ide tartrate) caused no alteration in ligand-accessible mD(1A) recepto rs, four of the full agonists (dopamine, dihydrexidine, dinapsoline, A 68930) caused a 30 to 40% reduction in receptor number. One full agoni st, 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 D-1 receptor was h omologous, not affecting beta-2 adrenergic receptors endogenous to C-6 cells. Neither incubation with cAMP analogs, nor inhibition of protei n kinase A, affected dopamine-induced desensitization, suggesting a cA MP-independent mechanism in this cell line. Together, these data sugge st that functional desensitization of the mD(1A) 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.