Plasma Membrane Na⁺-Coupled Citrate Transporter (SLC13A5) and Neonatal Epileptic Encephalopathy.
Plasma Membrane Na⁺-Coupled Citrate Transporter (SLC13A5) and Neonatal Epileptic Encephalopathy.
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DOI：
10.3390/molecules22030378
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发表时间：
2017-02-28
期刊：
影响因子：
--
通讯作者：
Ganapathy V
中科院分区：
文献类型：
--
作者：
Bhutia YD;Kopel JJ;Lawrence JJ;Neugebauer V;Ganapathy V
SLC13A5 是柠檬酸盐的 Na+ 偶联转运蛋白，在肝脏、睾丸和大脑中特定细胞类型的质膜中表达。它是一种生电转运蛋白，Na+:柠檬酸 3− 化学计量比为 4:1。在人类中，SLC13A5 转运柠檬酸盐的米氏常数约为 600 μM，考虑到血浆中柠檬酸盐的正常浓度在 150-200 μM 范围内，这在生理上是相关的。 Li+ 在锂治疗患者的治疗范围内的浓度下刺激人 SLC13A5 的转运功能。人类SLC13A5与啮齿动物Slc13a5的不同之处在于两个重要方面：人类转运蛋白对柠檬酸盐的亲和力比啮齿动物转运蛋白低约30倍，因此使人类SLC13A5成为低亲和力/高容量转运蛋白，而啮齿动物Slc13a5成为高亲和力/低容量转运蛋白。在肝脏中，SLC13A5 仅在肝细胞的肝窦膜中表达，在从肝窦血液中摄取循环柠檬酸盐以供代谢使用方面发挥作用。在睾丸中，转运蛋白仅在精子中表达，精子也只在线粒体所在的中段表达；精子中转运蛋白的可能功能是介导精液中高水平柠檬酸盐的摄取，以便随后在精子线粒体中代谢以产生生物能，从而支持精子活力。在大脑中，转运蛋白主要在神经元中表达。当星形胶质细胞将柠檬酸盐分泌到细胞外介质中时，SLC13A5在神经元中的潜在功能是介导循环柠檬酸盐的摄取和星形胶质细胞释放的柠檬酸盐以进行后续代谢。 Slc13a5敲除小鼠已生成；这些小鼠没有任何明显的表型，但对实验诱导的代谢综合征具有抵抗力。然而，最近发现人类 SLC13A5 的功能丧失突变会导致生命早期的严重癫痫和脑病。有趣的是，没有证据表明 Slc13a5 敲除小鼠患有癫痫或脑病，这突显了人类和小鼠之间这种转运蛋白功能丧失的临床后果的显着差异。人类 SLC13A5 和小鼠 SLC13a5 显着不同的生化特征可能导致人类和小鼠之间在转运蛋白缺陷的代谢后果方面存在差异。柠檬酸转运蛋白功能缺陷导致癫痫并损害神经元发育和功能的确切分子机制仍有待阐明，但现有文献表明 GABA（γ-氨基丁酸）信号传导功能障碍和 NMDA（N-甲基-d-天冬氨酸）受体信号传导功能亢进。讨论了将 SLC13A5 功能丧失突变与癫痫联系起来的可能突触机制。
SLC13A5 is a Na+-coupled transporter for citrate that is expressed in the plasma membrane of specific cell types in the liver, testis, and brain. It is an electrogenic transporter with a Na+:citrate3− stoichiometry of 4:1. In humans, the Michaelis constant for SLC13A5 to transport citrate is ~600 μM, which is physiologically relevant given that the normal concentration of citrate in plasma is in the range of 150–200 μM. Li+ stimulates the transport function of human SLC13A5 at concentrations that are in the therapeutic range in patients on lithium therapy. Human SLC13A5 differs from rodent Slc13a5 in two important aspects: the affinity of the human transporter for citrate is ~30-fold less than that of the rodent transporter, thus making human SLC13A5 a low-affinity/high-capacity transporter and the rodent Slc13a5 a high-affinity/low-capacity transporter. In the liver, SLC13A5 is expressed exclusively in the sinusoidal membrane of the hepatocytes, where it plays a role in the uptake of circulating citrate from the sinusoidal blood for metabolic use. In the testis, the transporter is expressed only in spermatozoa, which is also only in the mid piece where mitochondria are located; the likely function of the transporter in spermatozoa is to mediate the uptake of citrate present at high levels in the seminal fluid for subsequent metabolism in the sperm mitochondria to generate biological energy, thereby supporting sperm motility. In the brain, the transporter is expressed mostly in neurons. As astrocytes secrete citrate into extracellular medium, the potential function of SLC13A5 in neurons is to mediate the uptake of circulating citrate and astrocyte-released citrate for subsequent metabolism. Slc13a5-knockout mice have been generated; these mice do not have any overt phenotype but are resistant to experimentally induced metabolic syndrome. Recently however, loss-of-function mutations in human SLC13A5 have been found to cause severe epilepsy and encephalopathy early in life. Interestingly, there is no evidence of epilepsy or encephalopathy in Slc13a5-knockout mice, underlining the significant differences in clinical consequences of the loss of function of this transporter between humans and mice. The markedly different biochemical features of human SLC13A5 and mouse Slc13a5 likely contribute to these differences between humans and mice with regard to the metabolic consequences of the transporter deficiency. The exact molecular mechanisms by which the functional deficiency of the citrate transporter causes epilepsy and impairs neuronal development and function remain to be elucidated, but available literature implicate both dysfunction of GABA (γ-aminobutyrate) signaling and hyperfunction of NMDA (N-methyl-d-aspartate) receptor signaling. Plausible synaptic mechanisms linking loss-of-function mutations in SLC13A5 to epilepsy are discussed.
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DOI：
10.1152/ajpgi.00371.2006
发表时间：
2007-01-01
影响因子：
4.5
作者：
Gopal, Elangovan;Miyauchi, Seiji;Ganapathy, Vadivel
通讯作者：
Ganapathy, Vadivel
影响因子：
3.8
作者：
Goldschen-Ohm, Marcel P.;Haroldson, Alexander;Pearce, Robert A.
通讯作者：
Pearce, Robert A.
影响因子：
4.1
作者：
Inoue, K;Fei, YJ;Ganapathy, V
通讯作者：
Ganapathy, V
影响因子：
4.8
作者：
Inoue, K;Zhuang, L;Ganapathy, V
通讯作者：
Ganapathy, V
影响因子：
4.6
作者：
Huard K;Brown J;Jones JC;Cabral S;Futatsugi K;Gorgoglione M;Lanba A;Vera NB;Zhu Y;Yan Q;Zhou Y;Vernochet C;Riccardi K;Wolford A;Pirman D;Niosi M;Aspnes G;Herr M;Genung NE;Magee TV;Uccello DP;Loria P;Di L;Gosset JR;Hepworth D;Rolph T;Pfefferkorn JA;Erion DM
通讯作者：
Erion DM