Saugstad J A, Kinzie J M, Shinohara M M, Segerson T P, Westbrook G L
Vollum Institute for Advanced Biomedical Research, Oregon Health Sciences University, Portland 97201, USA.
Mol Pharmacol. 1997 Jan;51(1):119-25. doi: 10.1124/mol.51.1.119.
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-(carboxycyclopropyl)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)glycine approximately L-2-amino-4-phosphonobutyric acid > glutamate > > [1(S), 3(R)]-1-aminocyclopentane-1, 3-dicarboxylic acid, with EC50 values of 0.63, 0.67, 2.5, and 47 microM, 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.
代谢型谷氨酸受体（mGluR）的cDNA最初是从大鼠中克隆出来的，但编码mGluR8的小鼠cDNA克隆除外。小鼠mGluR8与腺苷酸环化酶的抑制作用偶联较弱，因此阻碍了其药理学特性的表征。我们分离出了一个编码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有显著表达。在大脑皮质、海马体、小脑和乳头体中检测到的表达较少。谷氨酸在共表达mGluR8和G蛋白偶联内向整流钾通道的非洲爪蟾卵母细胞中诱发了百日咳毒素敏感的钾电流。mGluR8也被III组特异性激动剂L-2-氨基-4-膦酰丁酸、常被用作选择性II组激动剂的(2(S), 1'(S), 2'(S)]-2-(羧基环丙基)甘氨酸以及非选择性激动剂(1(S), 3(R)]-1-氨基环戊烷-1,3-二羧酸激活，但不被I组特异性激动剂3,5-二羟基苯甘氨酸或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)甘氨酸激活。激动剂的效价顺序为[2(S), 1'(S), 2'(S)]-2-(羧基环丙基)甘氨酸≈L-2-氨基-4-膦酰丁酸>谷氨酸>>[1(S), 3(R)]-1-氨基环戊烷-1,3-二羧酸，其EC50值分别为0.63、0.67、2.5和47μM。I/II组特异性拮抗剂(R,S)-α-甲基-4-羧基苯甘氨酸和III组特异性拮抗剂α-甲基-氨基膦酰丁酸均抑制mGluR8。mGluR8的药理学特征在mGluR中是独特的，但在某些中枢神经系统途径中与突触前抑制的特征密切匹配。因此，在某些情况下，II组和III组激动剂介导的细胞反应可能反映了mGluR8的激活，而不是多种mGluR亚型的激活。
