MEDIATION OF CYCLIC-AMP SIGNALING BY THE FIRST INTRACELLULAR LOOP OF THE GONADOTROPIN-RELEASING-HORMONE RECEPTOR

The gonadotropin-releasing hormone (GnRH) receptor, which is a unique G protein-coupled receptor without a C-terminal cytoplasmic domain, ac tivates both inositol phosphate (InsP) and cAMP signaling responses. T he function of the highly basic first intracellular (1i) loop of the G nRH receptor in signal transduction was evaluated by mutating selected residues located in its N and C termini, Replacements of Leu(58), Lys (59), Gln(61), and Lys(62) at the N terminus, and Leu(73), Ser(74), an d Leu(80) at the C terminus, caused no change in binding affinity. The agonist-induced InsP and cAMP responses of the Q61E and K59Q,K62Q rec eptors were also unaffected, but the L58A receptor showed a normal Ins P response and an 80% decrease in cAMP production. At the C terminus, the InsP response of the L73R receptor was normal, but cAMP production was reduced by 80%, The EC50 for GnRH-induced InsP responses of the S 74E and L80A receptors was increased by about one order of magnitude, and the cAMP responses were essentially abolished. These findings indi cate that cAMP signaling from the GnRH receptor is dependent on specif ic residues in the 1i loop that are not essential for activation of th e phosphoinositide signaling pathway.