Functional Roles of Electrogenic Sodium Bicarbonate Cotransporter NBCe1 in Ocular Tissues

Suzuki, Masashi; Seki, George; Yamada, Hideomi; Horita, Shoko; Fujita, Toshiro

doi:10.2174/1874364101206010036

Cited by 12 publications

(11 citation statements)

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“…In one case, a 12-yr-old girl with a defect only in (renal) NBCe1-A variant did not have band keratopathy (412), consistent with variable penetrance or with the hypothesis that it is specifically a defect in NBCe1-B and -C in the corneal endothelium that causes the band keratopathy. If HCO 3 Ϫ secretion across the corneal endothelium and into the aqueous humor were compromised, a localized elevation of [HCO 3 Ϫ ] in the subepithelial region of the corneal stroma might be expected to enhance the deposition of Ca 2ϩ salts (928,989). Band keratopathy is not a feature associated with pRTA in individuals with the Q29X or R881C mutations (TABLE 6).…”

Section: I) Central Nervous System A) Mental Retardation Migraine mentioning

confidence: 99%

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

Parker

Boron

2013

Physiological Reviews

246

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: I) Central Nervous System A) Mental Retardation Migraine mentioning

confidence: 99%

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

Parker

Boron

2013

Physiological Reviews

246

262

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“…pRTA patients with homozygous NBCe1 mutations invariably presented with ocular abnormalities, typically consisting of band keratopathy, glaucoma, and cataract, indicating that the normal transport activity of NBCe1 in eye is indispensable for the maintenance of tissue homeostasis (Suzuki et al, 2012). …”

Section: Ocular Phenotypes Caused By Nbce1 Mutationsmentioning

confidence: 99%

“…It is well-known that the trabecular meshwork is the main site regulating aqueous outflow in the human eye (Bill, 1975). Accordingly, it is tempting to speculate that the inactivation of NBCe1 in trabecular meshwork cells may be responsible for the occurrence of high-tension glaucoma usually observed in the pRTA patients with homozygous NBCe1 mutations (Suzuki et al, 2010, 2012). Interestingly, the pRTA patient carrying the homozygous Q29X mutation also presented with bilateral high-tension glaucoma (Igarashi et al, 2001).…”

Section: Ocular Phenotypes Caused By Nbce1 Mutationsmentioning

confidence: 99%

Molecular mechanisms of renal and extrarenal manifestations caused by inactivation of the electrogenic Na+-HCO3− cotransporter NBCe1

Seki¹,

Horita²,

Suzuki³

et al. 2013

Front. Physiol.

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The electrogenic Na+-HCO3− cotransporter NBCe1 plays an essential role in bicarbonate absorption from renal proximal tubules, but also mediates the other biological processes in extrarenal tissues such as bicarbonate secretion from pancreatic ducts, maintenance of tissue homeostasis in eye, enamel maturation in teeth, or local pH regulation in synapses. Homozygous mutation in NBCe1 cause proximal renal tubular acidosis (pRTA) associated with extrarenal manifestations such as short stature, ocular abnormalities, enamel abnormalities, and migraine. Functional analyses of NBCe1 mutants using different expression systems suggest that at least a 50% reduction of the transport activity may be required to induce severe pRTA. In addition to functional impairments, some NBCe1 mutants show trafficking defects. Some of the pRTA-related NBCe1 mutants showing the cytoplasmic retention have been shown to exert a dominant negative effect through hetero-oligomer complexes with wild-type NBCe1 that may explain the occurrence of extrarenal manifestations in the heterozygous carries of NBCe1 mutations. Both NBCe1 knockout (KO) and W516X knockin (KI) mice showed very severe pRTA and reproduced most of the clinical manifestations observed in human pRTA patients. Functional analysis on isolated renal proximal tubules from W516X KI mice directly confirmed the indispensable role of NBCe1 in bicarbonate absorption from this nephron segment. In this review, we will focus on the molecular mechanisms underling the renal and extrarenal manifestations caused by NBCe1 inactivation.

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“…This mutation is separate among others found in the transmembrane domain (TMD) [7, 10]. The effect of the R298S mutation remains controversial in the literature.…”

Section: Introductionmentioning

confidence: 95%

“…Prior studies have demonstrated that NBCe1 variants also play a key role in maintaining ocular pressure and corneal clarity. NBCe1 defects in ocular tissue have been associated with glaucoma, band keratopathy (calcium deposition along the stroma), and cataracts [10, 11]. Additionally, NBCe1 variants participate in pH regulation of extracellular brain space, and are thought to modulate neuronal excitability in astrocytes by regulating local pH [12, 13].…”

Section: Introductionmentioning

confidence: 99%

Rescue of the temperature-sensitive, autosomal-recessive mutation R298S in the sodium-bicarbonate cotransporter NBCe1-A characterized by a weakened dimer and abnormal aggregation

Gill

Choi

Kammili

et al. 2015

Biochimica et Biophysica Acta (BBA) - General Subjects

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Background Band keratopathy, an ocular disease that is characterized by hypercalcemia and opaque bands across the cornea, has been associated with kidney disease. Type-II renal tubular acidosis (RTA), a condition in which the kidneys fail to recover bicarbonate (HCO3−) in the proximal tubule of the nephron, results in HCO3− wastage in the urine and low blood pH. The development of these diseases is associated with autosomal-recessive mutations in the Na+-coupled HCO3− cotransporter NBCe1-A located at the basolateral membranes of either cell type. Methods We provide insight into the devastating R298S mutation found in type-II RTA-afflicted individuals using confocal-microscopy imaging of fluorescently-tagged NBCe1-A and NBCe1-A-R298S molecules expressed in human corneal endothelial and proximal tubule cells and from in-depth biophysical studies of their cytoplasmic N-terminal domains (Nt and Nt-R298S), including Nt crystal structure, melting-temperature, and homodimer dissociation constant (KD) analyses. Results We illuminate and rescue trafficking defects of the R298S mutation of NBCe1-A. The KD for Nt monomer-dimer equilibrium is established. The KD for Nt-R298S is significantly higher, but immeasurable due to environmental factors (pH, temperature, concentration) that result in dimer instability leading to precipitation. The crystal structure of Nt-dimer shows that R298 is part of a putative substrate conduit and resides near the dimer interface held together by hydrogen-bond networks. Conclusions The R298S is a temperature-sensitive mutation in Nt that results in instability of the colloidal system leading to abnormal aggregation. General significance Our findings provide new perspectives to the aberrant mechanism of certain ocular pathologies and type-II RTA associated with the R298S mutation.

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Functional Roles of Electrogenic Sodium Bicarbonate Cotransporter NBCe1 in Ocular Tissues

Cited by 12 publications

References 59 publications

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

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

Molecular mechanisms of renal and extrarenal manifestations caused by inactivation of the electrogenic Na+-HCO3− cotransporter NBCe1

Rescue of the temperature-sensitive, autosomal-recessive mutation R298S in the sodium-bicarbonate cotransporter NBCe1-A characterized by a weakened dimer and abnormal aggregation

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