Takanaga Hitomi, Mackenzie Bryan, Suzuki Yoshiro, Hediger Matthias A
Membrane Biology Program and Renal Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
J Biol Chem. 2005 Mar 11;280(10):8974-84. doi: 10.1074/jbc.M413027200. Epub 2005 Jan 4.
Amino acid homeostasis depends on specific amino acid transport systems, many of which have been characterized at the molecular level. However, the classical System IMINO, defined as the Na+-dependent proline transport activity that escapes inhibition by alanine, had not been identified at the molecular level. We report here the functional characteristics and tissue distribution of Sodium/Imino-acid Transporter 1 (SIT1), which exhibits the properties of classical System IMINO. SIT1, the product of the slc6a20 gene, is a member of the SLC6 Na+- and Cl--dependent neurotransmitter transporter family whose function has remained unknown. When expressed in Xenopus oocytes, rat SIT1 mediated the uptake of imino acids such as proline (K0.5 approximately 0.2 mM) and pipecolate, as well as N-methylated amino acids (e.g. MeAIB, sarcosine). SIT1-mediated proline transport was pH-independent and insensitive to inhibition by alanine or lysine. Proline transport was Na+-dependent, Cl--stimulated, and voltage-dependent. Li+, but not H+, could substitute for Na+. Human SIT1 also functioned as a Na+-dependent proline transporter. Rat SIT1 mRNA was expressed in epithelial cells of duodenum, jejunum, ileum, stomach, cecum, colon, and kidney proximal tubule S 3 segments. SIT1 mRNA was also expressed in the choroid plexus, microglia, and meninges of the brain and in the ovary. Previous reports have documented the marked urinary hyperexcretion of proline in newborn rodents and man. We found that SIT1 was dramatically up-regulated in the kidneys of 3-day-old mice, accounting for the maturation of proline reabsorption in the mouse. The human slc6a20 gene coding SIT1 is an appropriate target for investigation of hereditary forms of iminoaciduria in man.
氨基酸稳态依赖于特定的氨基酸转运系统，其中许多已在分子水平上得到表征。然而，经典的IMINO系统，被定义为逃避丙氨酸抑制的钠依赖性脯氨酸转运活性，尚未在分子水平上被鉴定出来。我们在此报告钠/亚氨基酸转运体1（SIT1）的功能特性和组织分布，其表现出经典IMINO系统的特性。SIT1是slc6a20基因的产物，是SLC6钠和氯依赖性神经递质转运体家族的成员，其功能尚不清楚。当在非洲爪蟾卵母细胞中表达时，大鼠SIT1介导亚氨基酸如脯氨酸（K0.5约为0.2 mM）和哌可酸以及N-甲基化氨基酸（如甲基氨基异丁酸、肌氨酸）的摄取。SIT1介导的脯氨酸转运不依赖于pH，且对丙氨酸或赖氨酸的抑制不敏感。脯氨酸转运依赖于钠、受氯刺激且依赖于电压。锂离子而非氢离子可替代钠离子。人SIT1也作为钠依赖性脯氨酸转运体发挥作用。大鼠SIT1 mRNA在十二指肠、空肠、回肠、胃、盲肠、结肠和肾近端小管S3段的上皮细胞中表达。SIT1 mRNA也在脉络丛、小胶质细胞、脑的脑膜以及卵巢中表达。先前的报道记录了新生啮齿动物和人类中脯氨酸的显著尿排泄增加。我们发现SIT1在3日龄小鼠的肾脏中显著上调，这解释了小鼠中脯氨酸重吸收的成熟过程。编码SIT1的人slc6a20基因是研究人类亚氨基酸尿遗传形式的合适靶点。
