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首页> 外文期刊>Neurochemistry International: The International Journal for the Rapid Publication of Critical Reviews, Preliminary and Original Research Communications in Neurochemistry >Reciprocal inhibition of G-protein signaling is induced by CB(1) cannabinoid and GABA(B) receptor interactions in rat hippocampal membranes.
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Reciprocal inhibition of G-protein signaling is induced by CB(1) cannabinoid and GABA(B) receptor interactions in rat hippocampal membranes.

机译：G蛋白信号的相互抑制是由大鼠海马膜中的CB（1）大麻素和GABA（B）受体相互作用诱导的。

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Cannabinoid CB(1) and the metabotropic GABA(B) receptors have been shown to display similar pharmacological effects and co-localization in certain brain regions. Previous studies have reported a functional link between the two systems. As a first step to investigate the underlying molecular mechanism, here we show cross-inhibition of G-protein signaling between GABA(B) and CB(1) receptors in rat hippocampal membranes. The CB(1) agonist R-Win55,212-2 displayed high potency and efficacy in stimulating guanosine-5'-O-(3-[(35)S]thio)triphosphate, [(35)S]GTPgammaS binding. Its effect was completely blocked by the specific CB(1) antagonist AM251 suggesting that the signaling was via CB(1) receptors. The GABA(B) agonists baclofen and SKF97541 also elevated [(35)S]GTPgammaS binding by about 60%, with potency values in the micromolar range. Phaclofen behaved as a low potency antagonist with an ED(50) approximately 1mM. However, phaclofen at low doses (1 and 10nM) slightly but significantly attenuated maximal stimulation of [(35)S]GTPgammaS binding by the CB(1) agonist R-Win55,212-2. The observation that higher concentrations of phaclofen had no such effect rule out the possibility of its direct action on CB(1) receptors. The pharmacologically inactive stereoisomer S-Win55,212-3 had no effect either alone or in combination with phaclofen establishing that the interaction is stereospecific in hippocampus. The specific CB(1) antagonist AM251 at a low dose (1nM) also inhibited the efficacy of G-protein signaling of the GABA(B) receptor agonist SKF97541. Cross-talk of the two receptor systems was not detected in either spinal cord or cerebral cortex membranes. It is speculated that the interaction might occur via an allosteric interaction between a subset of GABA(B) and CB(1) receptors in rat hippocampal membranes. Although the exact molecular mechanism of the reciprocal inhibition between CB(1) and GABA(B) receptors will have to be explored by future studies it is intriguing that the cross-talk might be involved in balance tuning the endocannabinoid and GABAergic signaling in hippocampus.
机译：大麻素CB（1）和代谢型GABA（B）受体已显示在某些脑区域显示相似的药理作用和共定位。先前的研究已经报道了两个系统之间的功能联系。作为研究潜在分子机制的第一步，在这里我们显示了大鼠海马膜中GABA（B）和CB（1）受体之间的G蛋白信号交叉抑制。 CB（1）激动剂R-Win55,212-2在刺激鸟苷5'-O-（3-[（（35）S]硫代）三磷酸鸟嘌呤，[（35）S] GTPgammaS结合方面显示出高效能和功效。它的作用被特定的CB（1）拮抗剂AM251完全阻断，表明该信号传导是通过CB（1）受体进行的。 GABA（B）激动剂巴氯芬和SKF97541也将[（35）S] GTPgammaS结合提高了约60％，效力值在微摩尔范围内。 Phaclofen表现为低效拮抗剂，ED（50）约为1mM。但是，低剂量（1和10nM）下的phclofen对CB（1）激动剂R-Win55,212-2的[（35）S] GTPgammaS结合的最大刺激作用略微但明显减弱。观察到较高浓度的phaclofen没有这种作用，排除了其直接作用于CB（1）受体的可能性。药理学上无活性的立体异构体S-Win55,212-3单独使用或与phclofen联用均无作用，从而确定相互作用在海马体中是立体特异性的。低剂量（1nM）的特定CB（1）拮抗剂AM251也抑制GABA（B）受体激动剂SKF97541的G蛋白信号传导功效。在脊髓或大脑皮层膜中均未检测到两种受体系统的串扰。据推测，相互作用可能是通过大鼠海马膜中的一部分GABA（B）和CB（1）受体之间的变构相互作用而发生的。尽管将来的研究将必须探索CB（1）和GABA（B）受体之间相互抑制的确切分子机制，但有趣的是，这种相互影响可能与平衡调节海马中的内源性大麻素和GABA能信号有关。

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