Prézeau L, Carrette J, Helpap B, Curry K, Pin J P, Bockaert J
CNRS UPR 9023, Mécanismes Moléculaires des Communications Cellulaires, Centre CNRS-INSERM Pharmacologie-Endocrinologie, Montpellier, France.
Mol Pharmacol. 1994 Apr;45(4):570-7.
Several cDNAs coding for metabotropic glutamate receptors (mGluR1-7) have now been isolated. mGluR1 and -5 are positively coupled to phospholipase C, whereas mGluR2, -3, -4, -6, and -7 are negatively coupled to adenylyl cyclase (AC) when they are expressed in Chinese hamster ovary or baby hamster kidney cells. However, the exact transduction mechanisms of these receptors in their natural environment remain to be determined. In a previous work, we demonstrated that striatal neurons in primary culture expressed a mGluR that is negatively coupled to AC and that has a pharmacology different from that of mGluR2. In the present study, the pharmacology of mGluRs negatively coupled to AC in several neuronal types and in glial cells was compared with the pharmacology of mGluR2, -3, and -4. Like striatal neurons, cerebral cortical neurons express a mGluR that is able to inhibit AC both in intact cells and in membrane preparations, via a pertussis toxin-sensitive G protein. This mGluR has a pharmacological profile similar to that of mGluR3, because quisqualate is active at relatively low concentrations (EC50 < 100 microM). Similar experiments revealed that cerebellar granule cells expressed mGluR2-like and mGluR4-like receptors. Striatal glial cells also expressed a mGluR negatively coupled to AC via a pertussis toxin-sensitive G protein. However, only glutamate and aspartate, and not quisqualate, 2-(carboxycyclopropyl)glycine, trans-1-aminocyclopentane-1,3-dicarboxylate, or L-2-amino-4-phosphonobutyrate, were agonists for this glial mGluR. This pharmacology is different from that of any cloned mGluR. Reverse transcription associated with polymerase chain reaction revealed that mGluR2 and mGluR3 mRNAs are present in striatal, cortical, and cerebellar neurons but not in striatal glial cells. Interestingly, mGluR4 mRNA was found at a high level in cerebellar granule cells and at a lower level in cortical neurons and glial cells. However, the mGluR4-specific agonist L-2-amino-4-phosphonobutyrate was found to inhibit AC very slightly in granule cells only. In conclusion, our data show that mGluR2- and mGluR3-like receptors can directly inhibit AC in neurons, and they raise the question of whether mGluR4 is really negatively coupled to AC in its normal environment. We also present evidence for a new mGluR subtype expressed in glial cells.
目前已分离出几种编码代谢型谷氨酸受体（mGluR1 - 7）的cDNA。mGluR1和 - 5正向偶联至磷脂酶C，而mGluR2、 - 3、 - 4、 - 6和 - 7在中国仓鼠卵巢细胞或幼仓鼠肾细胞中表达时，负向偶联至腺苷酸环化酶（AC）。然而，这些受体在其自然环境中的具体转导机制仍有待确定。在之前的一项研究中，我们证明原代培养的纹状体神经元表达一种负向偶联至AC的mGluR，其药理学特性与mGluR2不同。在本研究中，将几种神经元类型和神经胶质细胞中负向偶联至AC的mGluR的药理学特性与mGluR2、 - 3和 - 4的药理学特性进行了比较。与纹状体神经元一样，大脑皮质神经元表达一种mGluR，该受体在完整细胞和膜制剂中均能通过百日咳毒素敏感的G蛋白抑制AC。这种mGluR的药理学特征与mGluR3相似，因为喹啉酸在相对较低浓度（EC50 < 100 microM）时具有活性。类似的实验表明，小脑颗粒细胞表达mGluR2样和mGluR4样受体。纹状体神经胶质细胞也表达一种通过百日咳毒素敏感的G蛋白负向偶联至AC的mGluR。然而，对于这种神经胶质mGluR，只有谷氨酸和天冬氨酸，而不是喹啉酸、2 - （羧基环丙基）甘氨酸、反式 - 1 - 氨基环戊烷 - 1,3 - 二羧酸或L - 2 - 氨基 - 4 - 膦酰丁酸是激动剂。这种药理学特性与任何克隆的mGluR都不同。逆转录聚合酶链反应显示，mGluR2和mGluR3 mRNA存在于纹状体、皮质和小脑神经元中，但不存在于纹状体神经胶质细胞中。有趣的是，在小脑颗粒细胞中发现mGluR4 mRNA水平较高，在皮质神经元和神经胶质细胞中水平较低。然而，发现mGluR4特异性激动剂L - 2 - 氨基 - 4 - 膦酰丁酸仅在颗粒细胞中对AC有非常轻微的抑制作用。总之，我们的数据表明mGluR2样和mGluR3样受体可直接在神经元中抑制AC，这也引发了mGluR4在其正常环境中是否真的负向偶联至AC的问题。我们还提供了在神经胶质细胞中表达的一种新的mGluR亚型的证据。
