Glucose transport by human renal Na+/D-glucose cotransporters SGLT1 and SGLT2
Glucose transport by human renal Na+/D-glucose cotransporters SGLT1 and SGLT2
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DOI：
10.1152/ajpcell.00388.2010
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发表时间：
2011-01-01
影响因子：
5.5
通讯作者：
Wright, Ernest M.
中科院分区：
文献类型：
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作者：
Hummel, Charles S.;Lu, Chuan;Wright, Ernest M.
Hummel CS，Lu C，Loo DD，Hirayama BA，Voss AA，Wright EM.人肾Na+/D-葡萄糖协同转运蛋白SGLT 1和SGLT 2的葡萄糖转运。美国生理学杂志细胞生理学300：C14-C21，2011年。首次出版于2010年10月27日; doi：10.1152/ajpcell. 00388.2010.-人Na+/D-葡萄糖协同转运蛋白2（hSGLT 2）被认为负责肾脏近曲小管中的大量葡萄糖重吸收。由于阻断重吸收增加尿糖排泄，hSGLT 2已成为2型糖尿病治疗的新药物靶点。使用全细胞膜片钳电生理学在37 ℃下在人胚肾293 T细胞中研究了hSGLT 2的葡萄糖转运。我们比较了hSGLT 2与hSGLT 1，直近端小管（S3段）中的转运蛋白。与hSGLT 1相比，hSGLT 2转运具有惊人相似的葡萄糖亲和力和较低的浓缩能力：hSGLT 2的Na+/D-葡萄糖共转运是产电的，表观葡萄糖和Na+亲和力为5和25 mM，Na+：葡萄糖偶联比为1; hSGLT 1亲和力为2和70 mM，偶联比为2。这两种蛋白质都显示出电压依赖性稳态转运;然而，与hSGLT 1不同，hSGLT 2没有表现出可检测到的响应于膜电压快速跳变的前稳态电流。D-半乳糖被两种蛋白质转运，但与hSGLT 2的亲和力非常低（>= 100 vs. 6 mM）。β-D-吡喃葡萄糖苷是底物或阻断剂。根皮苷与hSGLT 1相比，表现出与hSGLT 2更高的亲和力（Ki 11 vs. 140 nM）和更低的解离速率（0.03 vs. 0.2 s（-1））。这些研究表明，在早期近端小管中，hSGLT 2以50%的容量工作，仅当葡萄糖>= 35 mM时才饱和。此外，hSGLT 1的结果表明，它可能在晚期近端小管中过滤葡萄糖的重吸收中发挥重要作用。我们的电生理学研究为从分子水平了解hSGLT抑制剂如何影响肾脏葡萄糖重吸收提供了基础。
Hummel CS, Lu C, Loo DD, Hirayama BA, Voss AA, Wright EM. Glucose transport by human renal Na+/D-glucose cotransporters SGLT1 and SGLT2. Am J Physiol Cell Physiol 300: C14-C21, 2011. First published October 27, 2010; doi: 10.1152/ajpcell. 00388.2010.-The human Na+/D-glucose cotransporter 2 (hSGLT2) is believed to be responsible for the bulk of glucose reabsorption in the kidney proximal convoluted tubule. Since blocking reabsorption increases urinary glucose excretion, hSGLT2 has become a novel drug target for Type 2 diabetes treatment. Glucose transport by hSGLT2 was studied at 37 degrees C in human embryonic kidney 293T cells using whole cell patch-clamp electrophysiology. We compared hSGLT2 with hSGLT1, the transporter in the straight proximal tubule (S3 segment). hSGLT2 transports with surprisingly similar glucose affinity and lower concentrative power than hSGLT1: Na+/D-glucose cotransport by hSGLT2 was electrogenic with apparent glucose and Na+ affinities of 5 and 25 mM, and a Na+ : glucose coupling ratio of 1; hSGLT1 affinities were 2 and 70 mM and coupling ratio of 2. Both proteins showed voltage-dependent steady-state transport; however, unlike hSGLT1, hSGLT2 did not exhibit detectable pre-steady-state currents in response to rapid jumps in membrane voltage. D-Galactose was transported by both proteins, but with very low affinity by hSGLT2 (>= 100 vs. 6 mM). beta-D-Glucopyranosides were either substrates or blockers. Phlorizin exhibited higher affinity with hSGLT2 (K-i 11 vs. 140 nM) and a lower Off-rate (0.03 vs. 0.2 s(-1)) compared with hSGLT1. These studies indicate that, in the early proximal tubule, hSGLT2 works at 50% capacity and becomes saturated only when glucose is >= 35 mM. Furthermore, results on hSGLT1 suggest it may play a significant role in the reabsorption of filtered glucose in the late proximal tubule. Our electrophysiological study provides groundwork for a molecular understanding of how hSGLT inhibitors affect renal glucose reabsorption.