Arora K K, Krsmanovic L Z, Mores N, O'Farrell H, Catt K J
Endocrinology and Reproduction Research Branch, NICHD, National Institutes of Health, Bethesda, Maryland 20892, USA.
J Biol Chem. 1998 Oct 2;273(40):25581-6. doi: 10.1074/jbc.273.40.25581.
The gonadotropin-releasing hormone (GnRH) receptor, which is a unique G protein-coupled receptor without a C-terminal cytoplasmic domain, activates both inositol phosphate (InsP) and cAMP signaling responses. The function of the highly basic first intracellular (1i) loop of the GnRH receptor in signal transduction was evaluated by mutating selected residues located in its N and C termini. Replacements of Leu58, Lys59, Gln61, and Lys62 at the N terminus, and Leu73, Ser74, and Leu80 at the C terminus, caused no change in binding affinity. The agonist-induced InsP and cAMP responses of the Q61E and K59Q,K62Q receptors were also unaffected, but the L58A receptor showed a normal InsP 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 S74E and L80A receptors was increased by about one order of magnitude, and the cAMP responses were essentially abolished. These findings indicate that cAMP signaling from the GnRH receptor is dependent on specific residues in the 1i loop that are not essential for activation of the phosphoinositide signaling pathway.
促性腺激素释放激素（GnRH）受体是一种独特的G蛋白偶联受体，没有C末端胞质结构域，可激活肌醇磷酸（InsP）和cAMP信号反应。通过突变位于其N末端和C末端的特定残基，评估了GnRH受体高度碱性的第一个细胞内环（1i环）在信号转导中的功能。N末端的Leu58、Lys59、Gln61和Lys62以及C末端的Leu73、Ser74和Leu80的替换对结合亲和力没有影响。Q61E、K59Q和K62Q受体的激动剂诱导的InsP和cAMP反应也未受影响，但L58A受体显示出正常的InsP反应，而cAMP产生减少了80%。在C末端，L73R受体的InsP反应正常，但cAMP产生减少了80%。S74E和L80A受体的GnRH诱导的InsP反应的EC50增加了约一个数量级，并且cAMP反应基本被消除。这些发现表明，GnRH受体的cAMP信号传导依赖于1i环中的特定残基，这些残基对于磷酸肌醇信号通路的激活不是必需的。
