HCO3--independent conductance with a mutant Na+/HCO3-cotransporter (SLC4A4) in a case of proximal renal tubular acidosis with hypokalaemic paralysis
HCO3--independent conductance with a mutant Na+/HCO3-cotransporter (SLC4A4) in a case of proximal renal tubular acidosis with hypokalaemic paralysis
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DOI：
10.1113/jphysiol.2011.224733
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发表时间：
2012-04-01
影响因子：
5.5
通讯作者：
Boron, Walter F.
中科院分区：
文献类型：
--
作者：
Parker, Mark D.;Qin, Xue;Boron, Walter F.
突变型产电碳酸氢钠协同转运蛋白NBCe 1（A799 V）与肾脏无法调节血液pH值以及肌肉无力有关。在本研究中，我们采用生物素化和电生理学的非洲爪蟾卵母细胞以及非极化MDCK细胞的共聚焦显微镜。我们研究A799 V，加上三个实验室产生的突变体A799 G，A799 I和A799 S。A799 V和A799 I在MDCK细胞中显示增加的细胞内滞留。所有四个突变体表现出减少每分子Na+/HCO 3-共转运活性的卵母细胞。A799 V和A799 I表现出一种新的，DIDS刺激的，HCO 3-独立的电导的第一个例子在生电NBC。这一观察结果可能是A799 V对肌肉无力的贡献的基础。A799 G和A799 S表现出不寻常的外向整流。A799 G对DIDS和tenidap异常不敏感。因此，丙氨酸-799是正确NBCe 1功能的关键决定因素。
Key points A mutant electrogenic sodium bicarbonate cotransporter NBCe1 (A799V) is associated with an inability of the kidney to regulate blood pH as well as weakness of muscles. In the present study we employ biotinylation and electrophysiology on Xenopus oocytes as well as confocal microscopy on non-polarized MDCK cells. We study A799V, plus three laboratory-generated mutants A799G, A799I and A799S. A799V and A799I show increased intracellular retention in MDCK cells. All four mutants exhibit a reduced per-molecule Na+/HCO3- cotransport activity in oocytes. These observations probably underlie the inability of A799V to regulate blood pH. A799V and A799I exhibit a novel, DIDS-stimulated, HCO3--independent conductance the first example in an electrogenic NBC. This observation could underlie the contribution of A799V towards muscle weakness. A799G and A799S exhibit unusual outward rectification. A799G is unusually insensitive to DIDS and tenidap. Thus Alanine-799 is a critical determinant of correct NBCe1 function.