Missense mutation T485S alters NBCe1-A electrogenicity causing proximal renal tubular acidosis

Zhu, Qing; Shao, Xuesi M.; Kao, Liyo; Azimov, Rustam; Weinstein, Alan M.; Newman, Debra K.; liu, Weixin; Kurtz, Ira

doi:10.1152/ajpcell.00044.2013

Cited by 31 publications

(67 citation statements)

References 44 publications

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“…to Na ϩ -HCO 3 Ϫ cotransport (6). The human SLC4A4 gene encodes three NBCe1 protein variants (-A, -B, and -C), and additional transcripts (-D and -E) have been reported in mouse (7)(8)(9).…”

Section: ϫmentioning

confidence: 99%

“…Interestingly, the C-terminal tails from each monomer are closely associated in the cytosol, suggesting that they may have additional roles for NBCe1-A function (16). The transmembrane region of NBCe1-A contains 14 transmembrane segments (TMs) 2 with TM1, -3, and -8 involved in forming the ion permeation pathway (6,17,18) and TM10 -14 forming a scaffold structure to accommodate the ion interaction site (12) (see Fig. 1A).…”

Section: ϫmentioning

confidence: 99%

See 1 more Smart Citation

Interplay between Disulfide Bonding and N-Glycosylation Defines SLC4 Na+-coupled Transporter Extracellular Topography

Zhu¹,

Kao²,

Azimov³

et al. 2015

Journal of Biological Chemistry

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Section: ϫmentioning

confidence: 99%

Section: ϫmentioning

confidence: 99%

Interplay between Disulfide Bonding and N-Glycosylation Defines SLC4 Na+-coupled Transporter Extracellular Topography

Zhu¹,

Kao²,

Azimov³

et al. 2015

Journal of Biological Chemistry

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“…The direction of ion flux mediated by NBCe1-A in the proximal tubule is determined by the electrochemical driving force (μ) through the transporter, which is a function of the basolateral membrane potential, the substrate ion activities, and the NBCe1-A charge transport stoichiometry (407, 829). It has been implicitly assumed (in lieu of in vivo measurements of the native human transporter) that the NBCe1-A has charge transport stoichiometry of 1:3 (Na + -CO 3 2− -HCO 3 − cotransport mode) in the human proximal tubule largely based on in vivo measurements in other species (512, 564, 812).…”

Section: Proximal Tubulementioning

confidence: 99%

“…It has been implicitly assumed (in lieu of in vivo measurements of the native human transporter) that the NBCe1-A has charge transport stoichiometry of 1:3 (Na + -CO 3 2− -HCO 3 − cotransport mode) in the human proximal tubule largely based on in vivo measurements in other species (512, 564, 812). When expressed in a mammalian expression system (829) or oocytes (425), human NBCe1-A has a charge transport stoichiometry of 1:2. Various factors including phosphorylation state, (276), cell-type (275) and cell Ca 2+ (511) have been reported to modulate its value and yet the relevance of these findings to the proximal tubule in vivo is unclear.…”

Section: Proximal Tubulementioning

confidence: 99%

Molecular Mechanisms and Regulation of Urinary Acidification

Kurtz

2014

Comprehensive Physiology

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The H+ concentration in human blood is kept within very narrow limits, ~ 40 nM, despite the fact that dietary metabolism generates acid and base loads that are added to the systemic circulation throughout the life of mammals. One of the primary functions of the kidney is to maintain the constancy of systemic acid-base chemistry. The kidney has evolved the capacity to regulate blood acidity by performing three key functions: 1) reabsorb HCO3− that is filtered through the glomeruli to prevent its excretion in the urine; 2) generate a sufficient quantity of new HCO3− to compensate for the loss of HCO3− resulting from dietary metabolic H+ loads and loss of HCO3− in the urea cycle; and 3) excrete HCO3− (or metabolizable organic anions) following a systemic base load. The ability of the kidney to perform these functions requires that various cell types throughout the nephron respond to changes in acid-base chemistry by modulating specific ion transport and/or metabolic processes in a coordinated fashion such that the urine and renal vein chemistry is altered appropriately. The purpose of the article is to provide the interested reader with a broad review of a field that began historically ~ 60 years ago with whole animal studies, and has evolved to where we are currently addressing questions related to kidney acid-base regulation at the single protein structure/function level.

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“…An additional caveat in the attempt to reconstitute the TASK-2/NBCe1-A partnership in HEK-293 cells is the observation that the stoichiometry of the cotransporter can differ between the native location and the heterologous expression system. Indeed, Zhu et al have reported that when expressed in HEK-293 cells, NBCe1-A has a charge transport stoichiometry of 1:2 positive/negative charges, compatible with 1Na + /2HCO 3 − or 1 Na + /1CO 3 2− cotransport [64]. The differences in stoichiometry between native proximal tubule measurements, that mostly give a 1:3 charge stoichiometry, and that measured in heterologous systems, that can vary from 1:2 to 1:3 depending on the cell system or physiological state of the cells, have been discussed [49].…”

Section: Nbce1-a Our Demonstration Of Task-2 Protein Expression In Pmentioning

confidence: 99%

TASK-2 K2P K+ channel: thoughts about gating and its fitness to physiological function

López-Cayuqueo

Peña-Münzenmayer

Niemeyer

et al. 2014

Pflugers Arch - Eur J Physiol

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TASK-2 (K2P5) was one of the earliest members of the K2P two-pore, four transmembrane domain K(+) channels to be identified. TASK-2 gating is controlled by changes in both extra- and intracellular pH through separate sensors: arginine 224 and lysine 245, located at the extra- and intracellular ends of transmembrane domain 4. TASK-2 is inhibited by a direct effect of CO2 and is regulated by and interacts with G protein subunits. TASK-2 takes part in regulatory adjustments and is a mediator in the chemoreception process in neurons of the retrotrapezoid nucleus where its pHi sensitivity could be important in regulating excitability and therefore signalling of the O2/CO2 status. Extracellular pH increases brought about by HCO3 (-) efflux from proximal tubule epithelial cells have been proposed to couple to TASK-2 activation to maintain electrochemical gradients favourable to HCO3 (-) reabsorption. We demonstrate that, as suspected previously, TASK-2 is expressed at the basolateral membrane of the same proximal tubule cells that express apical membrane Na(+)-H(+)-exchanger NHE-3 and basolateral membrane Na(+)-HCO3 (-) cotransporter NBCe1-A, the main components of the HCO3 (-) transport machinery. We also discuss critically the mechanism by which TASK-2 is modulated and impacts the process of HCO3 (-) reclaim by the proximal tubule epithelium, concluding that more than a mere shift in extracellular pH is probably involved.

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Missense mutation T485S alters NBCe1-A electrogenicity causing proximal renal tubular acidosis

Abstract: I. Missense mutation T485S alters NBCe1-A electrogenicity causing proximal renal tubular acidosis.

Cited by 31 publications

References 44 publications

Interplay between Disulfide Bonding and N-Glycosylation Defines SLC4 Na+-coupled Transporter Extracellular Topography

Interplay between Disulfide Bonding and N-Glycosylation Defines SLC4 Na+-coupled Transporter Extracellular Topography

Molecular Mechanisms and Regulation of Urinary Acidification

TASK-2 K2P K+ channel: thoughts about gating and its fitness to physiological function

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