Department of Biotechnology and Life Science, Laboratory of Cellular and Molecular Physiology, University of Insubria, Via J. H. Dunant 3, 21100, Varese, Italy.
Center for Physiology and Pharmacology, Institute of Pharmacology, Medical University of Vienna, 1090, Vienna, Austria.
Cell Mol Life Sci. 2024 Jun 17;81(1):269. doi: 10.1007/s00018-024-05309-w.
Betaine is an endogenous osmolyte that exhibits therapeutic potential by mitigating various neurological disorders. However, the underlying cellular and molecular mechanisms responsible for its neuroprotective effects remain puzzling.In this study, we describe a possible mechanism behind the positive impact of betaine in preserving neurons from excitotoxicity. Here we demonstrate that betaine at low concentration modulates the GABA uptake by GAT1 (slc6a1), the predominant GABA transporter in the central nervous system. This modulation occurs through the temporal inhibition of the transporter, wherein prolonged occupancy by betaine impedes the swift transition of the transporter to the inward conformation. Importantly, the modulatory effect of betaine on GAT1 is reversible, as the blocking of GAT1 disappears with increased extracellular GABA. Using electrophysiology, mass spectroscopy, radiolabelled cellular assay, and molecular dynamics simulation we demonstrate that betaine has a dual role in GAT1: at mM concentration acts as a slow substrate, and at µM as a temporal blocker of GABA, when it is below its K. Given this unique modulatory characteristic and lack of any harmful side effects, betaine emerges as a promising neuromodulator of the inhibitory pathways improving GABA homeostasis via GAT1, thereby conferring neuroprotection against excitotoxicity.
甜菜碱是一种内源性渗透剂，通过减轻各种神经紊乱而显示出治疗潜力。然而，其神经保护作用的潜在细胞和分子机制仍令人费解。在这项研究中，我们描述了甜菜碱在保护神经元免受兴奋毒性方面的积极影响背后的一种可能机制。我们证明，低浓度的甜菜碱通过调节 GABA 摄取来调节 GAT1（slc6a1），GAT1 是中枢神经系统中主要的 GABA 转运体。这种调节是通过暂时抑制转运体来实现的，其中甜菜碱的长时间占据会阻碍转运体迅速向内构象转变。重要的是，甜菜碱对 GAT1 的调节作用是可逆的，因为随着细胞外 GABA 的增加，阻断 GAT1 的作用消失。我们使用电生理学、质谱、放射性标记细胞测定和分子动力学模拟来证明甜菜碱在 GAT1 中具有双重作用：在 mM 浓度下作为缓慢的底物，在 µM 浓度下作为 GABA 的瞬时阻断剂，当 GABA 低于其 K 时。鉴于这种独特的调节特性和缺乏任何有害的副作用，甜菜碱作为抑制途径的有前途的神经调节剂出现，通过 GAT1 改善 GABA 动态平衡，从而对兴奋毒性提供神经保护。
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