Vigot Réjan, Barbieri Samuel, Bräuner-Osborne Hans, Turecek Rostislav, Shigemoto Ryuichi, Zhang Yan-Ping, Luján Rafael, Jacobson Laura H, Biermann Barbara, Fritschy Jean-Marc, Vacher Claire-Marie, Müller Matthias, Sansig Gilles, Guetg Nicole, Cryan John F, Kaupmann Klemens, Gassmann Martin, Oertner Thomas G, Bettler Bernhard
Department of Clinical-Biological Sciences, Institute of Physiology, Pharmazentrum, University of Basel, CH-4056 Basel, Switzerland.
Neuron. 2006 May 18;50(4):589-601. doi: 10.1016/j.neuron.2006.04.014.
GABAB receptors are the G protein-coupled receptors for the main inhibitory neurotransmitter in the brain, gamma-aminobutyric acid (GABA). Molecular diversity in the GABAB system arises from the GABAB1a and GABAB1b subunit isoforms that solely differ in their ectodomains by a pair of sushi repeats that is unique to GABAB1a. Using a combined genetic, physiological, and morphological approach, we now demonstrate that GABAB1 isoforms localize to distinct synaptic sites and convey separate functions in vivo. At hippocampal CA3-to-CA1 synapses, GABAB1a assembles heteroreceptors inhibiting glutamate release, while predominantly GABAB1b mediates postsynaptic inhibition. Electron microscopy reveals a synaptic distribution of GABAB1 isoforms that agrees with the observed functional differences. Transfected CA3 neurons selectively express GABAB1a in distal axons, suggesting that the sushi repeats, a conserved protein interaction motif, specify heteroreceptor localization. The constitutive absence of GABAB1a but not GABAB1b results in impaired synaptic plasticity and hippocampus-dependent memory, emphasizing molecular differences in synaptic GABAB functions.
GABAB受体是大脑中主要抑制性神经递质γ-氨基丁酸（GABA）的G蛋白偶联受体。GABAB系统中的分子多样性源于GABAB1a和GABAB1b亚基异构体，它们仅在外显子区域因一对GABAB1a特有的寿司重复序列而有所不同。我们现在采用遗传学、生理学和形态学相结合的方法证明，GABAB1异构体定位于不同的突触位点，并在体内发挥不同的功能。在海马CA3到CA1突触处，GABAB1a组装异源受体抑制谷氨酸释放，而主要是GABAB1b介导突触后抑制。电子显微镜显示GABAB1异构体的突触分布与观察到的功能差异一致。转染的CA3神经元在远端轴突中选择性表达GABAB1a，这表明寿司重复序列（一种保守的蛋白质相互作用基序）决定了异源受体的定位。GABAB1a而非GABAB1b的组成性缺失导致突触可塑性受损和海马依赖性记忆受损，强调了突触GABAB功能的分子差异。
