A selective metabotropic glutamate receptor 7 agonist:: Activation of receptor signaling via an allosteric site modulates stress parameters in vivo
A selective metabotropic glutamate receptor 7 agonist:: Activation of receptor signaling via an allosteric site modulates stress parameters in vivo
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DOI：
10.1073/pnas.0508063102
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发表时间：
2005-12-20
影响因子：
11.1
通讯作者：
Flor, PJ
中科院分区：
文献类型：
--
作者：
Mitsukawa, K;Yamamoto, R;Flor, PJ
代谢型谷氨酸受体 (mGluR) 亚型（mGluR1 至 rnGluR8）是中枢神经系统神经传递的重要突触前和突触后调节因子。这些受体由两个结构域组成，一个包含正位激动剂位点的胞外区域和一个参与 G 蛋白激活和识别几种最近合成的药理调节剂的跨膜七螺旋结构域。突触前受体 mGluR7 在该家族中表现出最高的进化保守性，但尚无已知的选择性药理学工具。在这里，我们表征了一种 mGluR7 选择性激动剂 N,N'-二苯甲基乙烷-1,2-二胺二盐酸盐 (AMN082)，它通过跨膜结构域中的变构位点直接激活受体信号传导。在表达 mGluR7 的转染哺乳动物细胞中，AMN082 有效抑制 cAMP 积累并刺激 GTP γ S 结合（EC50 值，64-290 nM），其激动剂功效与 L-2-氨基-4-磷酸丁酸（L-AP(4)）相当，并且优于 L-谷氨酸。 AMN082（
Metabotropic glutamate receptor (mGluR) subtypes (mGluR1 to rnGluR8) act as important pre- and postsynaptic regulators of neurotransmission in the CNS. These receptors consist of two domains, an extracellular region containing the orthosteric agonist site and a transmembrane heptahelical domain involved in G protein activation and recognition of several recently synthesized pharmacological modulators. The presynaptic receptor mGluR7 shows the highest evolutionary conservation within the family, but no selective pharmacological tool was known. Here we characterize an mGluR7-selective agonist, N,N'-dibenzhydrylethane-1,2-diamine dihydrochloride (AMN082), which directly activates receptor signaling via an allosteric site in the transmembrane domain. At transfected mammalian cells expressing mGluR7, AMN082 potently inhibits cAMP accumulation and stimulates GTP gamma S binding (EC50-values, 64-290 nM) with agonist efficacies comparable with those Of L-2-amino-4-phosphonobutyrate (L-AP(4)) and superior to those of L-glutamate. AMN082 (