Cloning and expression of rat metabotropic glutamate receptor 8 reveals a distinct pharmacological profile
Cloning and expression of rat metabotropic glutamate receptor 8 reveals a distinct pharmacological profile
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DOI：
10.1124/mol.51.1.119
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发表时间：
1997-01-01
影响因子：
3.6
通讯作者：
Westbrook, GL
中科院分区：
文献类型：
--
作者：
Saugstad, JA;Kinzie, JM;Westbrook, GL
除编码mGluR8的小鼠cDNA克隆外，其他代谢性谷氨酸受体（mGluR） cDNA最初均克隆自大鼠。小鼠mGluR8对腺苷酸环化酶的抑制作用弱偶联，阻碍了其药理特性的表征。我们分离了一个编码908个氨基酸的大鼠mGluR8 cDNA。原位杂交显示，mGluR8 mRNA在嗅球、脑桥灰质、丘脑外侧网状核和梨状皮质中显著表达。在大脑皮层、海马、小脑和乳状体中表达量较少。谷氨酸在共表达mGluR8和G蛋白偶联的内向纠偏钾通道的非洲爪蟾卵母细胞中引起百日破毒素敏感钾电流。mGluR8也被iii组特异性激动剂l -2-氨基-4-磷酸丁酸激活；(2(S),1'(S),2'(S)]-2-（羧基环丙基）甘氨酸，它经常被用作选择性II族激动剂；非选择性激动剂(1(S),3(R)) -1-氨基环戊烷-1,3-二羧酸，而不是i组特异性激动剂3,5-二羟基苯基甘氨酸或ii组特异性激动剂[2(S),1'(R),2'(R),3(R)]-2-（2,3-二羧基环丙基）甘氨酸。激动剂的效价顺序为[2(S),1'(S),2'(S)]-2-（羧基环丙基）甘氨酸近似于l -2-氨基-4-磷酸丁酸>谷氨酸，远高于[1(S),3(R)]-1-氨基环戊烷-1,3-二羧酸，EC（50）值分别为0.63,0.67,2.5和47 μ M。I/ ii组特异性拮抗剂（R，S）- α -甲基-4-羧基苯基甘氨酸和iii组特异性拮抗剂- α -甲基-氨基膦丁酸均抑制mGluR8。mGluR8的药理学特征在mGluRs中是不同的，但与一些中枢神经系统通路的突触前抑制密切相关。因此，II组和III组激动剂介导的细胞反应在某些情况下可能反映mGluR8的激活，而不是多种mGluR亚型。
The metabotropic glutamate receptor (mGluR) cDNAs were originally cloned from rat, except for the mouse cDNA clone encoding mGluR8. Mouse mGluR8 couples weakly to the inhibition of adenylate cyclase, thus hindering the characterization of its pharmacological properties. We isolated a rat mGluR8 cDNA that encodes a protein of 908 amino acids. In situ hybridization revealed prominent mGluR8 mRNA expression in olfactory bulb, pontine gray, lateral reticular nucleus of the thalamus, and piriform cortex. Less abundant expression was detected in cerebral cortex, hippocampus, cerebellum, and mammillary body. Glutamate evoked pertussis toxin-sensitive potassium currents in Xenopus laevis oocytes coexpressing mGluR8 and G protein-coupled inwardly rectifying potassium channels. mGluR8 was also activated by the group III-specific agonist L-2-amino-4-phosphonobutyric acid; (2(S),1'(S),2'(S)]-2-(carboxycyclopropyI)glycine, which has been frequently used as a selective group II agonist; and the nonselective agonist (1(S),3(R)]-1-aminocyclopentane-1,3-dicarboxylic acid but not by the group I-specific agonist 3,5-dihydroxyphenylglycine or the group II-specific agonist [2(S),1'(R),2'(R),3(R)]-2-(2,3-dicarboxycyclopropyl)glycine. The agonist profile in order of potency was [2(S),1'(S),2'(S)]-2-(carboxycyclopropyl)glycin approximate to L-2-amino-4-phosphonobutyric acid > glutamate much greater than [1(S),3(R)]-1-aminocyclopentane-1,3-dicarboxylic acid, with EC(50) values of 0.63, 0.67, 2.5, and 47 mu M, respectively. Both the group I/II-specific antagonist (R,S)-alpha-methyl-4-carboxyphenylglycine and the group III-specific antagonist alpha-methyl-amino-phosphonobutyrate inhibited mGluR8. The pharmacological profile of mGluR8 is distinct among mGluRs but closely matches that of presynaptic inhibition in some central nervous system pathways. Thus, cellular responses mediated by both group II and III agonists may in some cases reflect activation of mGluR8 rather than multiple mGluR subtypes.