The betaine/GABA transporter and betaine: roles in brain, kidney, and liver.
The betaine/GABA transporter and betaine: roles in brain, kidney, and liver.
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DOI：
10.3389/fphys.2014.00159
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发表时间：
2014
影响因子：
4
通讯作者：
Danbolt NC
中科院分区：
文献类型：
--
作者：
Kempson SA;Zhou Y;Danbolt NC
甜菜碱/GABA 转运蛋白（BGT1；slc6a12）的生理作用仍在争论中。 BGT1 是溶质载体家族 6（神经递质、钠同向转运蛋白转运蛋白家族）的成员，在钠和氯依赖性过程中介导细胞对甜菜碱和 GABA 的摄取。 BGT1 的大多数研究都关注其在肾髓质中的功能和调节，在肾髓质中其作用最容易被理解。由于高渗透压以及高浓度的 NH4Cl 和尿素，这里的条件十分恶劣。为了承受高渗透压，细胞触发渗透适应，涉及细胞核中转录因子 TonEBP/NFAT5 的浓缩，并积累甜菜碱和其他渗透剂。来自培养物肾细胞（主要是 MDCK）的数据表明，TonEBP/NFAT5 对 BGT1 的转录调节相对较慢。为了更精确地控制质膜中 BGT1 蛋白的丰度，还存在依赖于细胞内钙和 ATP 的 BGT1 蛋白运输的翻译后调节。此外，甜菜碱作为甲基供体在肝脏代谢中可能很重要。事实上，小鼠的肝脏是 BGT1 含量最高的器官。肝细胞表达高水平的 BGT1 和唯一可以代谢甜菜碱的酶，即甜菜碱：同型半胱氨酸 -S-甲基转移酶 (BHMT1)。 BHMT1 酶可去除甜菜碱中的甲基，并将其转化为同型半胱氨酸，而同型半胱氨酸是心血管疾病的潜在危险因素。最后，BGT1 被认为在控制大脑兴奋性中发挥作用，从而成为抗惊厥药物开发的靶点。后一种假设存在争议，因为相对于大脑中其他 GABA 转运蛋白，BGT1 的表达水平非常低，而且 BGT1 的主要位置位于大脑表面的软脑膜中。这些问题都得到了详细讨论。
The physiological roles of the betaine/GABA transporter (BGT1; slc6a12) are still being debated. BGT1 is a member of the solute carrier family 6 (the neurotransmitter, sodium symporter transporter family) and mediates cellular uptake of betaine and GABA in a sodium- and chloride-dependent process. Most of the studies of BGT1 concern its function and regulation in the kidney medulla where its role is best understood. The conditions here are hostile due to hyperosmolarity and significant concentrations of NH4Cl and urea. To withstand the hyperosmolarity, cells trigger osmotic adaptation, involving concentration of a transcriptional factor TonEBP/NFAT5 in the nucleus, and accumulate betaine and other osmolytes. Data from renal cells in culture, primarily MDCK, revealed that transcriptional regulation of BGT1 by TonEBP/NFAT5 is relatively slow. To allow more acute control of the abundance of BGT1 protein in the plasma membrane, there is also post-translation regulation of BGT1 protein trafficking which is dependent on intracellular calcium and ATP. Further, betaine may be important in liver metabolism as a methyl donor. In fact, in the mouse the liver is the organ with the highest content of BGT1. Hepatocytes express high levels of both BGT1 and the only enzyme that can metabolize betaine, namely betaine:homocysteine –S-methyltransferase (BHMT1). The BHMT1 enzyme removes a methyl group from betaine and transfers it to homocysteine, a potential risk factor for cardiovascular disease. Finally, BGT1 has been proposed to play a role in controlling brain excitability and thereby represents a target for anticonvulsive drug development. The latter hypothesis is controversial due to very low expression levels of BGT1 relative to other GABA transporters in brain, and also the primary location of BGT1 at the surface of the brain in the leptomeninges. These issues are discussed in detail.
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