Native GABAB receptors are heteromultimers with a family of auxiliary subunits
Native GABAB receptors are heteromultimers with a family of auxiliary subunits
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DOI：
10.1038/nature08964
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发表时间：
2010-05-13
期刊：
影响因子：
64.8
通讯作者：
Bettler, Bernhard
中科院分区：
文献类型：
--
作者：
Schwenk, Jochen;Metz, Michaela;Bettler, Bernhard
GABA（B）受体是γ-氨基丁酸（GABA）的G蛋白偶联受体，GABA是脑中主要的抑制性神经递质。它们在大脑的几乎所有神经元中表达，在那里它们通过控制电压门控钙（Ca-v）和内向整流钾（K-ir）通道的活性来调节突触传递和信号传播（1）。分子克隆显示，功能性GABA（B）受体是由GABA（B1）与GABA（B2）亚基的异聚体组装形成的（2-5）。然而，克隆的GABA（B（1，2））受体不能再现用天然GABA（B）受体观察到的功能多样性（6-8）。在这里，我们通过功能蛋白质组学表明，GABA（B）受体在大脑中的GABA（B1），GABA（B2）和KCTD（钾通道四聚化结构域包含）蛋白质的一个亚家族的成员的高分子量的复合物。KCTD蛋白8、12、12 b和16在脑中显示出不同的表达谱，并与GABA（B2）的羧基末端紧密结合为四聚体。这种共组装改变了GABA（B（1，2））核心受体的性质：KCTD蛋白增加激动剂效力，并通过以KCTD亚型特异性方式加速发作和促进脱敏来显著改变受体的G蛋白信号传导。两者合计，我们的研究结果建立了KCTD蛋白作为辅助亚基的GABA（B）受体，确定药理学和动力学的受体反应。
GABA(B) receptors are the G-protein-coupled receptors for gamma-aminobutyric acid (GABA), the main inhibitory neurotransmitter in the brain. They are expressed in almost all neurons of the brain, where they regulate synaptic transmission and signal propagation by controlling the activity of voltage-gated calcium (Ca-v) and inward-rectifier potassium (K-ir) channels(1). Molecular cloning revealed that functional GABA(B) receptors are formed by the heteromeric assembly of GABA(B1) with GABA(B2) subunits(2-5). However, cloned GABA(B(1,2)) receptors failed to reproduce the functional diversity observed with native GABA(B) receptors(6-8). Here we show by functional proteomics that GABA(B) receptors in the brain are high-molecular-mass complexes of GABA(B1), GABA(B2) and members of a subfamily of the KCTD (potassium channel tetramerization domain-containing) proteins. KCTD proteins 8, 12, 12b and 16 show distinct expression profiles in the brain and associate tightly with the carboxy terminus of GABA(B2) as tetramers. This co-assembly changes the properties of the GABA(B(1,2)) core receptor: the KCTD proteins increase agonist potency and markedly alter the G-protein signalling of the receptors by accelerating onset and promoting desensitization in a KCTD-subtype-specific manner. Taken together, our results establish the KCTD proteins as auxiliary subunits of GABA(B) receptors that determine the pharmacology and kinetics of the receptor response.