Identification and characterization of a novel monoamine transporter in the human brain
Identification and characterization of a novel monoamine transporter in the human brain
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DOI：
10.1074/jbc.m407913200
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发表时间：
2004-11-26
影响因子：
4.8
通讯作者：
Wang, J
中科院分区：
文献类型：
--
作者：
Engel, K;Zhou, MY;Wang, J
精确控制脑细胞外液中单胺类神经递质水平对于维持有效和稳健的神经传递至关重要。溶质载体SLC6A家族中的高亲和转运蛋白在神经突触间隙中清除单胺的作用。新出现的证据表明，这些转运蛋白只是转运蛋白系统的一部分，转运蛋白系统协同工作以维持大脑单胺的稳态。在这里，我们报道了一个新的人质膜单胺转运蛋白PMAT的克隆和表征。PMAT cDNA编码一个由530个氨基酸残基组成的蛋白质，具有10 - 12个跨膜片段。PMAT与已知的神经递质转运蛋白不同源，但与平衡核苷转运蛋白家族的成员具有低同源性。当在Madin-Darby犬肾细胞和非洲爪蟾卵母细胞中表达时，PMAT可有效运输血清素（K-m = 114 muM）、多巴胺（K-m = 329 muM）和神经毒素1-甲基-4-苯基吡啶（K-m = 33 muM）。相比之下，PMAT与核苷或核碱基没有明显的相互作用。pmat介导的单胺转运不需要Na+或Cl-，但似乎对膜电位的变化很敏感。Northern blot分析显示，PMAT主要在人脑中表达，广泛分布于中枢神经系统。这些研究表明，PMAT可能是一种新的低亲和力的生物胺转运体，在一定条件下，它可能补充高亲和力转运体在大脑中的作用。
Precise control of monoamine neurotransmitter levels in the extracellular fluids of the brain is critical in maintaining efficient and robust neurotransmission. High affinity transporters in the solute carrier SLC6A family function in removing monoamines from the neurosynaptic cleft. Emerging evidence suggests that these transporters are only one part of a system of transporters that work in concert to maintain brain homeostasis of monoamines. Here we report the cloning and characterization of a new human plasma membrane monoamine transporter, PMAT. The PMAT cDNA encodes a protein of 530 amino acid residues with 10 - 12 transmembrane segments. PMAT is not homologous to known neurotransmitter transporters but exhibits low homology to members of the equilibrative nucleoside transporter family. When expressed in Madin-Darby canine kidney cells and Xenopus laevis oocytes, PMAT efficiently transports serotonin (K-m = 114 muM), dopamine (K-m = 329 muM), and the neurotoxin 1-methyl-4-phenylpyridinium (K-m = 33 muM). In contrast, there is no significant interaction of PMAT with nucleosides or nucleobases. PMAT-mediated monoamine transport does not require Na+ or Cl- but appears to be sensitive to changes in membrane potential. Northern blot analysis showed that PMAT is predominantly expressed in the human brain and widely distributed in the central nervous system. These studies demonstrate that PMAT may be a novel low affinity transporter for biogenic amines, which, under certain conditions, might supplement the role of the high affinity transporters in the brain.