Winder D G, Smith T, Conn P J
Department of Pharmacology, Emory University, Atlanta, Georgia.
J Pharmacol Exp Ther. 1993 Aug;266(2):518-25.
Activation of metabotropic glutamate receptors (mGluRs) results in multiple second messenger responses in rat hippocampal slices, including stimulation of phosphoinositide hydrolysis and potentiation of cyclic AMP responses induced by agonists of other receptors that are directly coupled to adenylate cyclase. Alpha 1 adrenergic receptors and H1-histaminergic receptors are similar to mGluRs in that agonists of these receptors also induce both phosphoinositide hydrolysis and potentiation of cyclic AMP responses to other agonists. In each of these cases, it is not clear whether activation of phosphoinositide hydrolysis and potentiation of cyclic AMP responses are mediated by the same or different receptor subtypes. In the present studies, the pharmacological profiles of mGluR-mediated potentiation of cyclic AMP responses and mGluR-mediated activation of phosphoinositide hydrolysis were compared to determine whether these responses are mediated by the same or distinct receptor subtypes. In addition, the authors determined the effect of mGluR activation on cyclic AMP responses in various regions of the rat brain and at different stages of postnatal development. It was found that the rank order of efficacies and potencies of mGluR agonists for potentiating cyclic AMP responses is distinct from the rank order of efficacies and potencies of the same compounds at stimulating phosphoinositide hydrolysis. Furthermore, L-serine-O-phosphate competitively blocked mGluR-mediated potentiation of cyclic AMP responses but had little or no effect on activation of phosphoinositide hydrolysis by the active isomer of trans-1-aminocyclopentane-1,3-dicarboxylic acid. These data are consistent with the hypothesis that these two responses are mediated by distinct mGluR subtypes.
代谢型谷氨酸受体（mGluRs）的激活在大鼠海马切片中引发多种第二信使反应，包括刺激磷酸肌醇水解以及增强由直接与腺苷酸环化酶偶联的其他受体激动剂诱导的环磷酸腺苷反应。α1肾上腺素能受体和H1组胺能受体与mGluRs相似，因为这些受体的激动剂也能诱导磷酸肌醇水解以及增强对其他激动剂的环磷酸腺苷反应。在上述每种情况下，尚不清楚磷酸肌醇水解的激活和环磷酸腺苷反应的增强是由相同还是不同的受体亚型介导。在本研究中，比较了mGluR介导的环磷酸腺苷反应增强和mGluR介导的磷酸肌醇水解激活的药理学特征，以确定这些反应是由相同还是不同的受体亚型介导。此外，作者还确定了mGluR激活对大鼠脑不同区域以及出生后不同发育阶段环磷酸腺苷反应的影响。结果发现，mGluR激动剂增强环磷酸腺苷反应的效能和效价顺序与这些化合物刺激磷酸肌醇水解的效能和效价顺序不同。此外，L-丝氨酸-O-磷酸竞争性阻断mGluR介导的环磷酸腺苷反应增强，但对反式-1-氨基环戊烷-1,3-二羧酸活性异构体激活磷酸肌醇水解几乎没有影响。这些数据与这两种反应由不同的mGluR亚型介导的假设一致。
