Transporter-dependent regulation of glycine neurotransmission in the respiratory network: the role of GlyT1 (SLC6A9) GlyT2 (SLC6A5) and Asc-1 (SLC7A10)

呼吸网络中甘氨酸神经传递的转运蛋白依赖性调节：GlyT1 (SLC6A9) GlyT2 (SLC6A5) 和 Asc-1 (SLC7A10) 的作用

• 批准号: 527924385
• 负责人: Professor Dr. Volker Eulenburg
• 金额: --
• 依托单位: Klinik für Anästhesiologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/527924385?language=en
• 关键词: Transporter; dependent; regulation; glycine; neurotransmission

Breathing is controlled by a neuronal network in the medulla and pons. Although the principal rhythm generator was shown to be glutamatergic, glycine-dependent neurotransmission exerts important modulatory functions and is critical for the coordinated activity of the respiratory network. The regulation of the extracellular glycine concentration is achieved by high affinity large capacity glycine transporters that mediate the transport of glycine across the membranes of presynaptic terminal or glial cells surrounding the synapse. Although most cells at glycine-dependent synapses express more than one transporter with high affinity for glycine, their functional interaction is only poorly understood. In this project, we now plan to investigated, how high affinity transporters for glycine, i.e. the predominantly astroglial expressed glycine transporter 1 (GlyT1; Slc6A9) and alanine-serine-cysteine-1 transporter (Asc-1; Slc7A10) and the neuronal expressed GlyT2 (Slc6a5) interact to regulate synapse homeostasis and how their contributions change during development. Thereby, we will not only foster our understand on the transporter functions per se, but will also extend our knowledge how glycine-dependent neurotransmission is involved in the regulation of the respiratory activity. In addition, it might provide novel insights on the mechanism how certain drugs like general anesthetics exert respiratory depressive effects. We are planning to tackle this topic by an interdisciplinary approach using genetically-modified mouse lines together with virus-based techniques and RNAi methods to manipulate the cellular expression of the different transporters. This will be combined with biochemical and physiological methods to allow the analysis of the respiratory activity in mice in-situ as well as in-vivo. Taken together this will help us to delineate the precise roles of the respective transporters at inhibitory synapses and describe in detail how these transporters interact functionally. This will include the description of the impact of respective transporters on glycine turnover at inhibitory glycinergic synapses. Thereby this project will enhance our understanding how transporter function correlates with alteration in synaptic transmission in respiratory neurons and with the breathing behavior.

呼吸是由脑髓和脑桥中的神经网络控制的。虽然主要的节律发生器被证明是谷氨酸，但甘氨酸依赖的神经传递具有重要的调节功能，对呼吸网络的协调活动至关重要。细胞外甘氨酸浓度的调节是通过高亲和力的大容量甘氨酸转运体来实现的，这些转运体介导甘氨酸穿过突触前末端或突触周围胶质细胞的膜。虽然大多数细胞在甘氨酸依赖突触表达一个以上的转运蛋白与甘氨酸高亲和力，他们的功能相互作用只是知之甚少。在这个项目中，我们现在计划研究甘氨酸的高亲和力转运体，即主要的星形胶质表达的甘氨酸转运体1 （GlyT1; Slc6A9）和丙氨酸-丝氨酸-半胱氨酸-1转运体（Asc-1; Slc7A10）和神经元表达的GlyT2 （Slc6a5）如何相互作用来调节突触稳态，以及它们的贡献在发育过程中如何变化。因此，我们不仅将促进我们对转运蛋白本身功能的理解，而且还将扩展我们对甘氨酸依赖的神经传递如何参与呼吸活动调节的认识。此外，它可能为某些药物（如全身麻醉剂）如何发挥呼吸抑制作用的机制提供新的见解。我们计划通过跨学科的方法来解决这个问题，使用转基因小鼠系，结合基于病毒的技术和RNAi方法来操纵不同转运体的细胞表达。这将与生物化学和生理方法相结合，以允许对小鼠的呼吸活动进行原位和体内的分析。综上所述，这将有助于我们描述各自转运蛋白在抑制性突触中的确切作用，并详细描述这些转运蛋白如何在功能上相互作用。这将包括各自的转运蛋白在抑制性甘氨酸能突触上对甘氨酸周转的影响的描述。因此，该项目将增强我们对转运蛋白功能如何与呼吸神经元突触传递改变和呼吸行为相关的理解。