Mediation of cyclic AMP signaling by the first intracellular loop of the gonadotropin-releasing hormone receptor
Mediation of cyclic AMP signaling by the first intracellular loop of the gonadotropin-releasing hormone receptor
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DOI：
10.1074/jbc.273.40.25581
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发表时间：
1998-10-02
影响因子：
4.8
通讯作者：
Catt, KJ
中科院分区：
文献类型：
--
作者：
Arora, KK;Krsmanovic, LZ;Catt, KJ
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，可激活磷酸肌醇（InsP）和cAMP信号传导反应。通过突变位于其N端和C端的选定残基来评价GnRH受体的高碱性第一胞内（1i）环在信号转导中的功能。N端的Leu（58）、Lys（59）、Gln（61）和Lys（62）以及C端的Leu（73）、Ser（74）和Leu（80）的替换未引起结合亲和力的变化。激动剂诱导的Q61E和K59Q、K62Q受体的InsP和cAMP反应也不受影响，但L58A受体显示出正常的InsP反应和80%的cAMP产生减少。在C端，L73R受体的InsP反应正常，但cAMP产生减少80%，S74E和L80A受体对GnRH诱导的InsP反应的EC_（50）增加约一个数量级，cAMP反应基本消失。这些发现表明，来自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传导途径的激活不是必需的。
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 Leu(58), Lys(59), Gln(61), and Lys(62) at the N terminus, and Leu(73), Ser(74), and 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 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.