Localization and Regulation of the ATP6V0A4 (a4) Vacuolar H+-ATPase Subunit Defective in an Inherited Form of Distal Renal Tubular Acidosis

Stehberger, Paul A.; Schulz, Nicole; Finberg, Karin E.; Karet, Fiona E.; Giebisch, Gerhard; Lifton, Richard P.; Geibel, John P.; Wagner, Carsten A.

doi:10.1097/01.asn.0000099375.74789.ab

Cited by 78 publications

(77 citation statements)

References 47 publications

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“…The main subtypes are alpha-ICs, which reduce acidosis by secreting protons into the lumen of the collecting duct, and beta-ICs, which reduce alkalosis by secreting bicarbonate. To function as polar opposites during pH regulation, these two subtypes differentially localize the H + vATPase along the apicobasal axis and differentially express the anion exchangers Ae1 and Pendrin (Royaux et al, 2001;Devonald et al, 2003;Stehberger et al, 2003;Stehberger et al, 2007;Hinton et al, 2009). How different subtypes of ICs form has been mainly addressed in the mammalian adult, in which, under chronic pH imbalances, the proportions of alpha-and beta-ICs appear to shift, leading to the suggestion that they are plastic and interconvertible (Al-Awqati, 1996;Schwartz et al, 2002;Wagner et al, 2002;Schwartz and Al-Awqati, 2005).…”

Section: Introductionmentioning

confidence: 99%

Specification of ion transport cells in theXenopuslarval skin

2011

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SUMMARYSpecialized epithelial cells in the amphibian skin play important roles in ion transport, but how they arise developmentally is largely unknown. Here we show that proton-secreting cells (PSCs) differentiate in the X. laevis larval skin soon after gastrulation, based on the expression of a 'kidney-specific' form of the H + v-ATPase that localizes to the plasma membrane, orthologs of the Cl -/HCO 3 -antiporters ae1 and pendrin, and two isoforms of carbonic anhydrase. Like PSCs in other species, we show that the expression of these genes is likely to be driven by an ortholog of foxi1, which is also sufficient to promote the formation of PSC precursors. Strikingly, the PSCs form in the skin as two distinct subtypes that resemble the alpha-and beta-intercalated cells of the kidney. The alpha-subtype expresses ae1 and localizes H + v-ATPases to the apical plasma membrane, whereas the beta-subtype expresses pendrin and localizes the H + v-ATPase cytosolically or basolaterally. These two subtypes are specified during early PSC differentiation by a binary switch that can be regulated by Notch signaling and by the expression of ubp1, a transcription factor of the grainyhead family. These results have implications for how PSCs are specified in vertebrates and become functionally heterogeneous.

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Section: Introductionmentioning

confidence: 99%

Specification of ion transport cells in theXenopuslarval skin

2011

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“…As both P Ca and P Mg are increased in the presence of claudin-10b, this isoform appears to be of major importance to the resorption of divalent cations. Potential interactions between claudin-10b and the two claudins that have already been linked to Mg 2+ resorption, claudin-16 and 19 (Müller et al, 2003;Kausalya et al, 2006;Hou et al, 2008) (for a review, see van de Graaf et al, 2007) are therefore highly interesting and will be subject of future experiments.…”

Section: +mentioning

confidence: 99%

“…Tubular segments were isolated and first strand cDNA was made as described previously (Stehberger et al, 2003;Smith et al, 2005). Although PCT (proximal convoluted tubule, mTAL medullary thick ascending limb of Henle's loop), CCD, OMCD and IMCD (cortical, outer and inner medullary collecting duct) were unequivocally identified, glomeruli appeared to be contaminated with macula densa and/or DCT material (judged from the presence of NKCC2 and NCC mRNA) and were therefore omitted from the present analyses.…”

Section: Rt-pcr On Dissected Mouse Nephron Segmentsmentioning

confidence: 99%

Claudin-10 exists in six alternatively spliced isoforms that exhibit distinct localization and function

Günzel

Stuiver

Kausalya

et al. 2009

Journal of Cell Science

171

198

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cells, transfection of high-resistance MDCK-C7 cells withCldn10b dramatically decreased transepithelial resistance, increased cation permeability, and changed monovalent cation selectivity from Eisenman sequence IV to X, indicating the presence of a high field-strength binding site that almost completely removes the hydration shell of the permeating cations. The extent of all these effects strongly depended on the endogenous claudins of the transfected cells. Supplementary material available online at

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“…Vph1p is localized to the vacuole, whereas Stv1p is found primarily in Golgi (11,12). The mammalian a subunit has four isoforms, a1-4; a1, a2, and a3 are ubiquitously expressed, but to different degrees in different tissues and organelles, whereas a4 expression appears to be specific to plasma membranes of renal intercalated cells (9,(13)(14)(15). Although ubiquitously expressed, a3 appears to be most highly enriched in osteoclasts (9).…”

Section: V-atpasesmentioning

confidence: 99%

Osteopetrosis Mutation R444L Causes Endoplasmic Reticulum Retention and Misprocessing of Vacuolar H+-ATPase a3 Subunit

Bhargava

Voronov

Wang

et al. 2012

Journal of Biological Chemistry

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Background:The human V-ATPase a3 subunit mutation, R444L, causes infantile malignant osteopetrosis. Results: In mouse, the R444L equivalent, R445L, causes endoplasmic reticulum retention, misprocessing, and defective trafficking of a3 to the plasma membrane. Conclusion: Arginine 444/445 plays a critical role in mammalian a3 folding, or stability. Significance: R444L a3 infantile malignant osteopetrosis is a protein folding disease that may be amenable to protein rescue therapy.

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Localization and Regulation of the ATP6V0A4 (a4) Vacuolar H+-ATPase Subunit Defective in an Inherited Form of Distal Renal Tubular Acidosis

Cited by 78 publications

References 47 publications

Specification of ion transport cells in theXenopuslarval skin

Specification of ion transport cells in theXenopuslarval skin

Claudin-10 exists in six alternatively spliced isoforms that exhibit distinct localization and function

Osteopetrosis Mutation R444L Causes Endoplasmic Reticulum Retention and Misprocessing of Vacuolar H+-ATPase a3 Subunit

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