Betz H, Gomeza J, Armsen W, Scholze P, Eulenburg V
Department of Neurochemistry, Max-Planck-Institute for Brain Research, Deutschordenstrasse 46, 60528 Frankfurt, Germany.
Biochem Soc Trans. 2006 Feb;34(Pt 1):55-8. doi: 10.1042/BST0340055.
Glycine is a major inhibitory neurotransmitter in the mammalian CNS (central nervous system). Glycinergic neurotransmission is terminated by the uptake of glycine into glycinergic nerve terminals and neighbouring glial cells. This uptake process is mediated by specific Na(+)/Cl(-)-dependent GlyTs (glycine transporters), GlyT1 and GlyT2. GlyT1, in addition, is thought to regulate the concentration of glycine at excitatory synapses containing NMDARs (N-methyl-D-aspartate receptors), which require glycine as a co-agonist. We have analysed the physiological roles and regulation of GlyT1 and GlyT2 by generating transporter-deficient mice and searching for interacting proteins. Our genetic results indicate that at glycinergic synapses, the glial transporter GlyT1 catalyses the removal of glycine from the synaptic cleft, whereas GlyT2 is required for the re-uptake of glycine into nerve terminals, thereby allowing for neurotransmitter reloading of synaptic vesicles. Both GlyT1 and GlyT2 are essential for CNS function, as revealed by the lethal phenotypes of the respective knockout mice. Mice expressing only a single GlyT1 allele are phenotypically normal but may have enhanced NMDAR function. GlyT2 is highly enriched at glycinergic nerve terminals, and Ca(2+)-triggered exocytosis and internalization are thought to regulate GlyT2 numbers in the pre-synaptic plasma membrane. We have identified different interacting proteins that may play a role in GlyT2 trafficking and/or pre-synaptic localization.
甘氨酸是哺乳动物中枢神经系统（CNS）中的一种主要抑制性神经递质。甘氨酸能神经传递通过甘氨酸被摄取到甘氨酸能神经末梢和邻近的神经胶质细胞中而终止。这种摄取过程由特定的依赖Na⁺/Cl⁻的甘氨酸转运体（GlyTs），即GlyT1和GlyT2介导。此外，GlyT1被认为可调节含有N-甲基-D-天冬氨酸受体（NMDARs）的兴奋性突触处的甘氨酸浓度，NMDARs需要甘氨酸作为共激动剂。我们通过生成转运体缺陷小鼠并寻找相互作用蛋白，分析了GlyT1和GlyT2的生理作用及调控机制。我们的遗传学结果表明，在甘氨酸能突触处，神经胶质转运体GlyT1催化从突触间隙清除甘氨酸，而GlyT2是甘氨酸重新摄取到神经末梢所必需的，从而使神经递质重新装载到突触小泡中。如各自基因敲除小鼠的致死表型所示，GlyT1和GlyT2对中枢神经系统功能均至关重要。仅表达单个GlyT1等位基因的小鼠在表型上是正常的，但可能具有增强的NMDAR功能。GlyT2在甘氨酸能神经末梢高度富集，并且Ca²⁺触发的胞吐作用和内化作用被认为可调节突触前质膜中GlyT2的数量。我们已经鉴定出了不同的相互作用蛋白，它们可能在GlyT2的运输和/或突触前定位中发挥作用。
