THE HUMAN AND DOG 5-HT(1D) RECEPTORS CAN BOTH ACTIVATE AND INHIBIT ADENYLATE-CYCLASE IN TRANSFECTED CELLS

The cloned human serotonin 1D (5-HT1D) receptor has been shown to inhibit adenylate cyclase while the corresponding cloned dog receptor has been characterized by its enhancement of cAMP accumulation. To resolve this apparent discrepancy, the human 5-HT1D receptor has been cloned and expressed in Chinese hamster ovary (CHO) cells and the corresponding dog receptor expressed in mutant Y1 adrenal (Y1 Kin-8) cells. It is shown that both receptors when activated by sumatriptan depress forskolin induced adenosine 3'5'-cyclic monophosphate (cAMP) accumulation by a pertussis toxin sensitive mechanism, presumably involving G(i) (the adenylate cyclase inhibitory GTP transducing protein). In the absence of forskolin, the dog receptor enhances cAMP accumulation, thus activating G(s) (the adenylate cyclase stimulatory GTP transducing protein). When its overriding action on G(i) is blocked by pertussis toxin pretreatment, the human receptor also enhances cAMP accumulation. Thus both 5-HT1D receptors activate markedly G(i) and to a lesser extent G(s) and can exert opposite effects on the same effector system, adenylate cyclase.