Characterization of a family of endogenous neuropeptide ligands for the G protein-coupled receptors GPR7 and GPR8
Characterization of a family of endogenous neuropeptide ligands for the G protein-coupled receptors GPR7 and GPR8
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DOI：
10.1073/pnas.0837789100
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发表时间：
2003-05-13
影响因子：
11.1
通讯作者：
Yanagisawa, M
中科院分区：
文献类型：
--
作者：
Tanaka, H;Yoshida, T;Yanagisawa, M
GPR 7和GPR 8是孤儿G蛋白偶联受体，彼此高度相似。这些受体主要在脑中表达，表明在中枢神经系统功能中的作用。我们已经从牛下丘脑提取物中纯化了GPR 7的内源性肽配体。这种肽称为神经肽B（NPB），在N末端有一个C-6-溴化色氨酸残基。它结合并激活人GPR 7或GPR 8，中位有效浓度（EC 50）分别为0.23 nM和15.8 nM。原位杂交显示prepro-NPB mRNA在小鼠脑中的不同定位，即，下丘脑室旁核、海马及中脑和脑干的几个核团。脑室内（i. c. v.）在小鼠中注射NPB在最初的2小时期间诱导摄食过多，随后是摄食不足。侧脑室注射NPB对s.c.福尔马林注射。通过EST数据库检索，我们确定了一个推定的旁系同源肽。这种肽被称为神经肽W（NPW），也具有N-末端色氨酸残基。合成人NPW结合并激活人GPR 7或GPR 8，EC 50值分别为0.56 nM和0.51 nM。NPW mRNA在小鼠脑内的表达局限于中脑和脑干的特定核团。这些发现表明NPB和NPW在中枢神经系统中具有不同的生理功能，作为GPR 7和/或GPR 8的内源性配体。
GPR7 and GPR8 are orphan G protein-coupled receptors that are highly similar to each other. These receptors are expressed predominantly in brain, suggesting roles in central nervous system function. We have purified an endogenous peptide ligand for GPR7 from bovine hypothalamus extracts. This peptide, termed neuropeptide B (NPB), has a C-6-brominated tryptophan residue at the N terminus. It binds and activates human GPR7 or GPR8 with median effective concentrations (EC50) of 0.23 nM and 15.8 nM, respectively. In situ hybridization shows distinct localizations of the prepro-NPB mRNA in mouse brain, i.e., in paraventricular hypothalamic nucleus, hippocampus, and several nuclei in midbrain and brainstem. Intracerebroventricular (i.c.v.) injection of NPB in mice induces hyperphagia during the first 2 h, followed by hypophagia. Intracerebroventricular injection of NPB produces analgesia to s.c. formalin injection in rats. Through EST database searches, we identified a putative paralogous peptide. This peptide, termed neuropeptide W (NPW), also has an N-terminal tryptophan residue. Synthetic human NPW binds and activates human GPR7 or GPR8 with EC50 values of 0.56 nM and 0.51 nM, respectively. The expression of NPW mRNA in mouse brain is confined to specific nuclei in midbrain and brainstem. These findings suggest diverse physiological functions of NPB and NPW in the central nervous system, acting as endogenous ligands on GPR7 and/or GPR8.