Jones K A, Borowsky B, Tamm J A, Craig D A, Durkin M M, Dai M, Yao W J, Johnson M, Gunwaldsen C, Huang L Y, Tang C, Shen Q, Salon J A, Morse K, Laz T, Smith K E, Nagarathnam D, Noble S A, Branchek T A, Gerald C
Synaptic Pharmaceutical Corporation, Paramus, New Jersey 07652, USA.
Nature. 1998 Dec 17;396(6712):674-9. doi: 10.1038/25348.
The principal inhibitory neurotransmitter GABA (gamma-aminobutyric acid) exerts its effects through two ligand-gated channels, GABA(A) and GABA(C) receptors, and a third receptor, GABA(B) , which acts through G proteins to regulate potassium and calcium channels. Cells heterologously expressing the cloned DNA encoding the GABA(B)R1 protein exhibit high-affinity antagonist-binding sites, but they produce little of the functional activity expected from studies of endogenous GABA(B) receptors in the brain. Here we describe a new member of the GABA(B) polypeptide family, GABA(B)R2, that shows sequence homology to GABA(B)R1. Neither GABA(B)R1 nor GABA(B)R2, when expressed individually, activates GIRK-type potassium channels; however, the combination of GABA(B)R1 and GABA(B)R2 confers robust stimulation of channel activity. Both genes are co-expressed in individual neurons, and both proteins co-localize in transfected cells. Moreover, immunoprecipitation experiments indicate that the two polypeptides associate with each other, probably as heterodimers. Several G-protein-coupled receptors (GPCRs) exist as high-molecular-weight species, consistent with the formation of dimers by these receptors, but the relevance of these species for the functioning of GPCRs has not been established. We have now shown that co-expression of two GPCR structures, GABA(B)R1 and GABA(B)R2, belonging to the same subfamily is essential for signal transduction by GABA(B) receptors.
主要的抑制性神经递质γ-氨基丁酸（GABA）通过两种配体门控通道即GABA(A)和GABA(C)受体以及第三种受体GABA(B)发挥作用，GABA(B)受体通过G蛋白调节钾通道和钙通道。异源表达编码GABA(B)R1蛋白的克隆DNA的细胞表现出高亲和力拮抗剂结合位点，但它们产生的功能活性远低于对脑内源性GABA(B)受体研究预期的水平。在此，我们描述了GABA(B)多肽家族的一个新成员GABA(B)R2，它与GABA(B)R1具有序列同源性。单独表达时，GABA(B)R1和GABA(B)R2均不能激活GIRK型钾通道；然而，GABA(B)R1与GABA(B)R2的组合能有力地刺激通道活性。这两个基因在单个神经元中共表达，两种蛋白在转染细胞中也共定位。此外，免疫沉淀实验表明这两种多肽相互结合，可能形成异二聚体。几种G蛋白偶联受体（GPCR）以高分子量形式存在，这与这些受体形成二聚体一致，但这些形式与GPCR功能的相关性尚未确定。我们现已表明，属于同一亚家族的两种GPCR结构即GABA(B)R1和GABA(B)R2的共表达对GABA(B)受体的信号转导至关重要。
