Dutar P, Nicoll R A
Department of Pharmacology, University of California, San Francisco 94143.
Nature. 1988 Mar 10;332(6160):156-8. doi: 10.1038/332156a0.
The role of GABA in synaptic transmission in the mammalian central nervous system is more firmly established than for any other neurotransmitter. With virtually every neuron studied, the synaptic action of GABA is mediated by bicuculline-sensitive GABAA receptors which selectively increase chloride conductance. However, it has been shown that GABA has a presynaptic inhibitory action on transmitter release that is insensiive to bicuculline and is selectively mimicked by baclofen. The receptors involved in this action are referred to as GABAB receptors, to distinguish them from the classic bicuculline-sensitive GABAA receptors. In hippocampal pyramidal cells an additional postsynaptic action of GABA and baclofen has been reported that is also insensitive to GABAA antagonists, and may be mediated by GABAB receptors on the postsynaptic neuron. This action of GABA and baclofen involves an increase in potassium conductance. Synaptic activation of pathways converging on hippocampal pyramidal cells results in a slow inhibitory postsynaptic potential which involves an increase in potassium conductance, and it has been suggested that GABAB receptors might be responsible for this synaptic potential. However, to establish convincingly that GABAB receptors are physiologically important in the central nervous system, a selective GABAB antagonist is required. Here we provide this missing evidence. Using the hippocampal slice preparation, we now report that the phosphonic acid derivative of baclofen, phaclofen, is a remarkably selective antagonist of both the postsynaptic action of baclofen and the bicuculline-resistant action of GABA, and that it selectively abolishes the slow inhibitory postsynaptic potential in pyramidal cells.
γ-氨基丁酸（GABA）在哺乳动物中枢神经系统突触传递中的作用比其他任何神经递质都更确切。几乎对每一个研究过的神经元而言，GABA的突触作用是由荷包牡丹碱敏感的GABAA受体介导的，该受体可选择性增加氯离子电导。然而，已有研究表明，GABA对递质释放具有突触前抑制作用，这种作用对荷包牡丹碱不敏感，且能被巴氯芬选择性模拟。参与此作用的受体被称为GABAB受体，以区别于经典的对荷包牡丹碱敏感的GABAA受体。据报道，在海马锥体细胞中，GABA和巴氯芬还有一种额外的突触后作用，该作用对GABAA拮抗剂也不敏感，可能由突触后神经元上的GABAB受体介导。GABA和巴氯芬的这种作用涉及钾离子电导增加。汇聚于海马锥体细胞的通路发生突触激活会导致缓慢的抑制性突触后电位，该电位涉及钾离子电导增加，有人提出GABAB受体可能是产生这种突触电位的原因。然而，要令人信服地证实GABAB受体在中枢神经系统中具有重要生理功能，就需要一种选择性GABAB拮抗剂。在此我们提供了这一缺失的证据。利用海马脑片标本，我们现在报告，巴氯芬的膦酸衍生物法氯芬是巴氯芬突触后作用和GABA对荷包牡丹碱耐药作用的一种非常选择性的拮抗剂，它能选择性消除锥体细胞中的缓慢抑制性突触后电位。
