PIP2 hydrolysis stimulates the electrogenic Na+–bicarbonate cotransporter NBCe1‐B and ‐C variants expressed in Xenopus laevis oocytes

Thornell, Ian M.; Wu, Jianping; Liu, Xiaofen; Bevensee, Mark O.

doi:10.1113/jphysiol.2012.242479

Cited by 23 publications

(46 citation statements)

References 35 publications

(64 reference statements)

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“…Application of PIP 2 to the intracellular face of excised Xenopus oocytes patches containing NBCe1-A stimulates transport (1049). However, PIP 2 is rapidly hydrolyzed when injected into intact oocytes, an observation that may explain why injection of PIP 2 does not result in the stimulation of NBCe1-A in whole cells (968).…”

Section: Ncbt Stimulationmentioning

confidence: 99%

The Divergence, Actions, Roles, and Relatives of Sodium-Coupled Bicarbonate Transporters

Parker

Boron

2013

Physiological Reviews

241

262

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The mammalian Slc4 (Solute carrier 4) family of transporters is a functionally diverse group of 10 multi-spanning membrane proteins that includes three Cl-HCO3 exchangers (AE1-3), five Na(+)-coupled HCO3(-) transporters (NCBTs), and two other unusual members (AE4, BTR1). In this review, we mainly focus on the five mammalian NCBTs-NBCe1, NBCe2, NBCn1, NDCBE, and NBCn2. Each plays a specialized role in maintaining intracellular pH and, by contributing to the movement of HCO3(-) across epithelia, in maintaining whole-body pH and otherwise contributing to epithelial transport. Disruptions involving NCBT genes are linked to blindness, deafness, proximal renal tubular acidosis, mental retardation, and epilepsy. We also review AE1-3, AE4, and BTR1, addressing their relevance to the study of NCBTs. This review draws together recent advances in our understanding of the phylogenetic origins and physiological relevance of NCBTs and their progenitors. Underlying these advances is progress in such diverse disciplines as physiology, molecular biology, genetics, immunocytochemistry, proteomics, and structural biology. This review highlights the key similarities and differences between individual NCBTs and the genes that encode them and also clarifies the sometimes confusing NCBT nomenclature.

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Section: Ncbt Stimulationmentioning

confidence: 99%

The Divergence, Actions, Roles, and Relatives of Sodium-Coupled Bicarbonate Transporters

Parker

Boron

2013

Physiological Reviews

241

262

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“…PIP 2 which can also activate the transporter may bind to the same motif as IRBIT [47]. PIP 2 mediated activation of NBCe1-B and –C appears to involve a staurosporine-sensitive kinase [119]. Of interest, PIP 2 also activates NBCe1-A (and potentially NBCe1-D) however the mechanism remains undetermined [129].…”

Section: Modulation Of Nbce1 Functionmentioning

confidence: 99%

NBCe1 as a model carrier for understanding the structure–function properties of Na+-coupled SLC4 transporters in health and disease

Kurtz¹

2014

Pflugers Arch - Eur J Physiol

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SLC4 transporters are membrane proteins that in general mediate the coupled transport of bicarbonate (carbonate) and share amino acid sequence homology. These proteins differ as to whether they also transport Na+ and/or Cl−, in addition to their charge transport stoichiometry, membrane targeting, substrate affinities, developmental expression, regulatory motifs, and protein-protein interactions. These differences account in part for the fact that functionally, SLC4 transporters have various physiological roles in mammals including transepithelial bicarbonate transport, intracellular pH regulation, transport of Na+ and/or Cl−, and possibly water. Bicarbonate transport is not unique to the SLC4 family since the structurally unrelated SLC26 family has at least three proteins that mediate Cl−-HCO3− exchange. The present review focuses on the first of the sodium-dependent SLC4 transporters that was identified whose structure has been most extensively studied: the electrogenic Na+-base cotransporter NBCe1. Mutations in NBCe1 cause proximal renal tubular acidosis (pRTA) with neurologic and ophthalmologic extrarenal manifestations. Recent studies have characterized important structure-function properties of the transporter and how they are perturbed as a result of mutations that cause pRTA. It has become increasingly apparent that the structure of NBCe1 differs in several key features from the SLC4 Cl−-HCO3− exchanger AE1 whose structural properties have been well-studied. In this review, the structure-function properties and regulation of NBCe1 will be highlighted and its role in health and disease will be reviewed in detail.

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“…The function of NBCe1 variants has been reported to be regulated by protein kinase A (PKA)/cAMP [30, 61], protein kinase C (PKC) [62], Mg 2+ [63, 64], Ca 2+ [32], ATP [40], carbonic anhydrases I–III [65], IRBIT [66], and PIP 2 [5]. Several studies have begun to elucidate the differences among NBCe1 variants in their regulatory mechanisms that offer potential targets in the future for clinically modulating their transport function pharmacologically.…”

Section: Functional Regulation Of Nbce1mentioning

confidence: 99%

“…PIP 2 directly stimulates the activity of NBCe1-A and indirectly stimulates the NBCe1-B and -C via an increase in IP 3 /Ca 2+ involving a staurosporine-sensitive kinase [5, 68]. …”

Section: Functional Regulation Of Nbce1mentioning

confidence: 99%

“…The gene encodes 3 human variants (-A, -B, and -C) and recently additional variants (-D and -E) have been reported in mouse [4]. Importantly, all three NBCe1 variants in humans (which have different N- and C-terminal sequences) mediate electrogenic Na + -HCO 3 − transport, but differ in their tissue expression, intrinsic activity, and regulation [5]. In kidney, NBCe1-A is the key transporter predominantly expressed in S1 and S2 proximal tubule cells that mediates basolateral Na + -base efflux thereby contributing to the reabsorption of ~80% of the filtered bicarbonate load [6].…”

Section: Introductionmentioning

confidence: 99%

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Structure, function, and regulation of the SLC4 NBCe1 transporter and its role in causing proximal renal tubular acidosis

Kurtz¹,

Zhu²

2013

Current Opinion in Nephrology and Hypertension

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Purpose of review There has been significant progress in our understanding of the structural and functional properties and regulation of NBCe1, a membrane transporter that plays a key role in renal acid-base physiology. NBCe1-A mediates basolateral electrogenic sodium-base transport in the proximal tubule and is critically required for transepithelial bicarbonate absorption. Mutations in NBCe1 cause autosomal recessive proximal renal tubular acidosis (pRTA). The review summarizes recent advances in this area. Recent findings A topological model of NBCe1 has been established that provides a foundation for future structure-functional studies of the transporter. Critical residues and regions have been identified in NBCe1 that play key roles in its structure, function (substrate transport, electrogenicity) and regulation. The mechanisms of how NBC1 mutations cause pRTA have also recently been elucidated. Summary Given the important role of proximal tubule transepithelial bicarbonate absorption in systemic acid-base balance, a clear understanding of the structure-functional properties of the NBCe1-A is a prerequisite for elucidating the mechanisms of defective transepithelial bicarbonate transport in pRTA.

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PIP₂ hydrolysis stimulates the electrogenic Na⁺–bicarbonate cotransporter NBCe1‐B and ‐C variants expressed in Xenopus laevis oocytes

Cited by 23 publications

References 35 publications

The Divergence, Actions, Roles, and Relatives of Sodium-Coupled Bicarbonate Transporters

The Divergence, Actions, Roles, and Relatives of Sodium-Coupled Bicarbonate Transporters

NBCe1 as a model carrier for understanding the structure–function properties of Na+-coupled SLC4 transporters in health and disease

Structure, function, and regulation of the SLC4 NBCe1 transporter and its role in causing proximal renal tubular acidosis

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