Schoepp D D, Salhoff C R, Wright R A, Johnson B G, Burnett J P, Mayne N G, Belagaje R, Wu S, Monn J A
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA.
Neuropharmacology. 1996;35(12):1661-72. doi: 10.1016/s0028-3908(96)00121-9.
The mGlu receptor subtypes and second messenger pathways that mediate 1S,3R-1-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD) responses in brain tissues are not fully understood. 1S,3R-ACPD differs from 3,5-dihydroxyphenylglycine (DHPG) or quisqualate in that 1S,3R-ACPD also activates group 2 mGlu receptors (mGlu2 and mGlu3) that are negatively linked to cAMP formation. To investigate the contribution of group 2 mGlu receptor activity of 1S,3R-ACPD to the phosphoinositide response in the rat hippocampus, we examined the effects of the novel group 2 mGlu receptor agonist 2R,4R-4-aminopyrrolidine-2,4-dicarboxylate (2R,4R-APDC). 2R,4R-APDC did not activate or inhibit group 1 mGlu receptors (human mGlu1 alpha and mGlu5a) or group 3 mGlu receptors (human mGlu4 and mGlu7), but potently decreased forskolin-stimulated cAMP formation in human mGlu2- and mGlu3-expressing cells. In slices of the adult rat hippocampus 2R,4R-APDC had no effect on basal phosphoinositide hydrolysis; however, it was found to greatly enhance phosphoinositide hydrolysis to DHPG or quisqualate. In the neonatal rat hippocampus, 2R,4R-APDC enhanced the potency of DHPG, while not affecting the maximal response to group 1 mGlu receptor agonists. Thus, the phosphoinositide response in the rat hippocampus to 1S,3R-ACPD is mediated by a synergistic interaction between group 1 and group 2 mGlu receptors.
介导脑组织中1S,3R - 1 - 氨基环戊烷 - 1,3 - 二羧酸（1S,3R - ACPD）反应的代谢型谷氨酸（mGlu）受体亚型和第二信使途径尚未完全明确。1S,3R - ACPD与3,5 - 二羟基苯甘氨酸（DHPG）或喹啉酸不同，因为1S,3R - ACPD还能激活与环磷酸腺苷（cAMP）形成呈负相关的2组mGlu受体（mGlu2和mGlu3）。为研究1S,3R - ACPD的2组mGlu受体活性对大鼠海马体中磷酸肌醇反应的作用，我们检测了新型2组mGlu受体激动剂2R,4R - 4 - 氨基吡咯烷 - 2,4 - 二羧酸（2R,4R - APDC）的作用。2R,4R - APDC不会激活或抑制1组mGlu受体（人mGlu1α和mGlu5a）或3组mGlu受体（人mGlu4和mGlu7），但能有效降低佛司可林刺激的、表达人mGlu2和mGlu3的细胞中的cAMP生成。在成年大鼠海马体切片中，2R,4R - APDC对基础磷酸肌醇水解没有影响；然而，发现它能极大地增强对DHPG或喹啉酸的磷酸肌醇水解。在新生大鼠海马体中，2R,4R - APDC增强了DHPG的效力，同时不影响对1组mGlu受体激动剂的最大反应。因此，大鼠海马体中对1S,3R - ACPD的磷酸肌醇反应是由1组和2组mGlu受体之间的协同相互作用介导的。
