Dept. Biomedicine, Institute of Physiology, University of Basel, 4056 Basel, Switzerland.
Dept. Biomedicine, Institute of Physiology, University of Basel, 4056 Basel, Switzerland.
Neuropharmacology. 2018 Jul 1;136(Pt A):106-116. doi: 10.1016/j.neuropharm.2017.10.033. Epub 2017 Oct 26.
Following the discovery of GABA receptors by Norman Bowery and colleagues, cloning and biochemical efforts revealed that GABA receptors assemble multi-subunit complexes composed of principal and auxiliary subunits. The principal receptor subunits GABA, GABA and GABA form two heterodimeric GABA and GABA receptors that can associate with tetramers of auxiliary KCTD (K channel tetramerization domain) subunits. Experiments with subunit knock-out mice revealed that GABA receptors activate slow inhibitory postsynaptic currents (sIPSCs) while GABA receptors function as heteroreceptors and inhibit glutamate release. Both GABA and GABA receptors can serve as autoreceptors and inhibit GABA release. Auxiliary KCTD subunits regulate the duration of sIPSCs and scaffold effector channels at the receptor. GABA receptors are well known to contribute to thalamic spindle oscillations. Spindles are generated through alternating burst-firing in reciprocally connected glutamatergic thalamocortical relay (TCR) and GABAergic thalamic reticular nucleus (TRN) neurons. The available data implicate postsynaptic GABA receptors in TCR cells in the regulation of spindle frequency. We now used electrical or optogenetic activation of thalamic spindles and pharmacological experiments in acute slices of knock-out mice to study the impact of GABA and GABA receptors on spindle oscillations. We found that selectively GABA heteroreceptors at TCR to TRN cell synapses regulate oscillation strength, while GABA receptors control oscillation frequency. The auxiliary subunit KCTD16 influences both oscillation strength and frequency, supporting that KCTD16 regulates network activity through GABA and GABA receptors. This article is part of the "Special Issue Dedicated to Norman G. Bowery".
继 Norman Bowery 及其同事发现 GABA 受体之后，通过克隆和生化研究揭示 GABA 受体由主亚基和辅助亚基组成多亚基复合物。主亚基 GABA、GABA 和 GABA 形成两种异二聚体 GABA 和 GABA 受体，可与辅助 KCTD（K 通道四聚化结构域）亚基的四聚体结合。利用亚基敲除小鼠的实验表明，GABA 受体激活缓慢抑制性突触后电流（sIPSCs），而 GABA 受体作为异受体抑制谷氨酸释放。GABA 和 GABA 受体均可作为自身受体抑制 GABA 释放。辅助 KCTD 亚基调节 sIPSCs 的持续时间并在受体处作为支架效应器通道。众所周知，GABA 受体有助于丘脑纺锤波振荡。纺锤波通过互传谷氨酸能丘脑皮质中继（TCR）和 GABA 能丘脑网状核（TRN）神经元的交替爆发式放电产生。现有数据表明，突触后 GABA 受体参与 TCR 细胞中纺锤波频率的调节。我们现在使用电或光遗传学方法激活丘脑纺锤波，并在敲除小鼠的急性切片中进行药理学实验，以研究 GABA 和 GABA 受体对纺锤波振荡的影响。我们发现，选择性地在 TCR 至 TRN 细胞突触的 GABA 异受体调节振荡强度，而 GABA 受体控制振荡频率。辅助亚基 KCTD16 影响振荡强度和频率，表明 KCTD16 通过 GABA 和 GABA 受体调节网络活动。本文是“Norman G. Bowery 特刊”的一部分。
