Partial Agonist Clonidine Mediates α2-AR Subtypes Specific Regulation of cAMP Accumulation in Adenylyl Cyclase II Transfected DDT1-MF2 Cells

α2-Adrenergic receptor (α 2 -AR) activation in the pregnant rat myometrium at midterm potentiates β 2 -AR stimulation of adenylyl cyclase (AC) via Gβγ regulation of the type II isoform of adenylyl cyclase. However, at term, α 2 -AR activation inhibits β 2 -AR stimulation of AC. This phenomenon is associated with changes in α 2 -AR subtype expression (midterm α 2A/D -AR ≫ α 2B -AR; term α 2B ≥ α 2A/D -AR), without any change in ACII mRNA, suggesting that α 2A/D - and α 2B -AR differentially regulate β 2 -cAMP production. To address this issue, we have stably expressed the same density of α 2A/D - or α 2B -AR with AC II in DDT1-MF2 cells. Clonidine (partial agonist) increased β 2 -AR-stimulated cAMP production in α 2A/D -AR-ACII transfectants but inhibited it in α 2B -AR-ACII transfectants. In contrast, epinephrine (full agonist) enhanced β 2 -stimulated ACII in both α 2A - and α 2B -ACII clonal cell lines. 4-Azidoanilido-[α- 32 P]GTP-labeling of activated G proteins indicated that, in α 2B -AR transfectants, clonidine activated only Gi 2 , whereas epinephrine, the full agonist, effectively coupled to Gi 2 and Gi 3 . Thus, partial and full agonists selectively activate G proteins that lead to drug specific effects on effectors. Moreover, these data indicate that Gi 3 activation is required for potentiation of β 2 -AR stimulation of AC by α 2A/D and α 2B -AR in DDT1-MF2 cells. This may reflect an issue of the amount of Gβγ released upon receptor activation and/or βγ composition of Gi 3 versus Gi 2 .