Novel mGluR- and CB1R-independent suppression of GABA release caused by a contaminant of the group I metabotropic glutamate receptor agonist, DHPG.
Novel mGluR- and CB1R-independent suppression of GABA release caused by a contaminant of the group I metabotropic glutamate receptor agonist, DHPG.
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DOI：
10.1371/journal.pone.0006122
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发表时间：
2009-07-01
期刊：
影响因子：
3.7
通讯作者：
Alger BE
中科院分区：
文献类型：
--
作者：
Lafourcade CA;Zhang L;Alger BE
代谢型谷氨酸受体（mGluRs）普遍存在于全身，特别是在脑中，在脑中它们介导许多作用。MGluR被分为几组，其中第I组包括mGluR 1和5，在神经元通讯中特别重要。I组的行动往往是研究与选择性激动剂，S-3，5-二羟基苯甘氨酸（DHPG）。尽管DHPG的选择性，它的使用往往导致矛盾的结果。我们现在报告说，一个特定的商业制剂DHPG可以产生mGluR独立的影响。这些发现可能有助于调和一些不一致的报告。我们在大鼠离体海马脑片制备中进行了电生理记录，主要集中在分离的GABA A受体介导的突触电流。主要发现：虽然来自三家公司的DHPG制剂以mGluR依赖性方式抑制GABA能传输，但一批产品具有额外的不寻常效果。即使在存在mGluRs拮抗剂的情况下，它也会对抑制性传递产生可逆的、深刻的抑制。这种mGluR非依赖性作用不是由于化合物的更高效力或其引起内源性大麻素依赖性反应的能力。场电位记录显示，GABA能传输不受影响，GABA传输的量子分析证实了不寻常的影响是对GABA的释放，而不是GABAA受体。我们尚未确定DHPG制备中的负责因素，但通过HPLC和NMR分析测定，样品纯度为99%。在某些方面，我们对异常批次的观察与一些发表的关于不寻常DHPG效应的报告惊人地相似。因此，本研究结果可能有助于解释文献中的差异。DHPG被广泛用于研究不同系统中的mGluRs，因此在得出基于其使用的结论之前应进行严格的控制。
Metabotropic glutamate receptors (mGluRs) are ubiquitous throughout the body, especially in brain, where they mediate numerous effects. MGluRs are classified into groups of which group I, comprising mGluRs 1 and 5, is especially important in neuronal communication. Group I actions are often investigated with the selective agonist, S-3,5-dihydroxyphenylglycine (DHPG). Despite the selectivity of DHPG, its use has often led to contradictory findings. We now report that a particular commercial preparation of DHPG can produce mGluR-independent effects. These findings may help reconcile some discrepant reports. We carried out electrophysiological recordings in the rat in vitro hippocampal slice preparation, focusing mainly on pharmacologically isolated GABAA-receptor-mediated synaptic currents. Principal Findings: While preparations of DHPG from three companies suppressed GABAergic transmission in an mGluR-dependent way, one batch had an additional, unusual effect. Even in the presence of antagonists of mGluRs, it caused a reversible, profound suppression of inhibitory transmission. This mGluR - independent action was not due to a higher potency of the compound, or its ability to cause endocannabinoid-dependent responses. Field potential recordings revealed that glutamatergic transmission was not affected, and quantal analysis of GABA transmission confirmed the unusual effect was on GABA release, and not GABAA receptors. We have not identified the responsible factor in the DHPG preparation, but the samples were 99% pure as determined by HPLC and NMR analyses. In certain respects our observations with the anomalous batch strikingly resemble some published reports of unusual DHPG effects. The present findings could therefore contribute to explaining discrepancies in the literature. DHPG is widely employed to study mGluRs in different systems, hence rigorous controls should be performed before conclusions based on its use are drawn.
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