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Vacuolar H⁺-ATPase d2 Subunit: Molecular Characterization, Developmental Regulation, and Localization to Specialized Proton Pumps in Kidney and Bone

Annabel N. Smith^*, François Jouret^||, Sharyn Bord, Katherine J. Borthwick^*, Rafia S. Al-Lamki, Carsten A. Wagner^¶, Deborah C. Ireland, Valerie Cormier-Daire^#, Annalisa Frattini^**, Anna Villa^**, Uwe Kornak, Olivier Devuyst^|| and Fiona E. Karet^*,

Departments of ^* Medical Genetics and Medicine and Division of Renal Medicine, University of Cambridge, Cambridge, United Kingdom; ^|| Division of Nephrology, Université catholique de Louvain, Brussels, Belgium; ^¶ Institute of Physiology, University of Zurich, Zurich, Switzerland; ^# Department of Medical Genetics, Hôpital Necker, Paris, France; ^** Istituto di Tecnologie Biomediche, Milan, Italy; and Institute for Medical Genetics, Charité University Hospital, Berlin, Germany

Address correspondence to: Dr. Fiona Karet, Cambridge Institute for Medical Research, Box 139 Addenbrooke’s Hospital, Cambridge, CB2 2XY, UK. Phone: +44-1223-762617; Fax: +44-1223-331206; fek1000{at}cam.ac.uk

Received for publication September 13, 2004. Accepted for publication February 15, 2005.

The ubiquitous multisubunit vacuolar-type proton pump (H⁺- or V-ATPase) is essential for acidification of diverse intracellular compartments. It is also present in specialized forms at the plasma membrane of intercalated cells in the distal nephron, where it is required for urine acidification, and in osteoclasts, playing an important role in bone resorption by acid secretion across the ruffled border membrane. It was reported previously that, in human, several of the renal pump’s constituent subunits are encoded by genes that are different from those that are ubiquitously expressed. These paralogous proteins may be important in differential functions, targeting or regulation of H⁺-ATPases. They include the d subunit, where d1 is ubiquitous whereas d2 has a limited tissue expression. This article reports on an investigation of d2. It was first confirmed that in mouse, as in human, kidney and bone are two of the main sites of d2 mRNA expression. d2 mRNA and protein appear later during nephrogenesis than does the ubiquitously expressed E1 subunit. Mouse nephron-segment reverse transcription–PCR revealed detectable mRNA in all segments except thin limb of Henle’s loop and distal convoluted tubule. However, with the use of a novel d2-specific antibody, high-intensity d2 staining was observed only in intercalated cells of the collecting duct in fresh-frozen human kidney, where it co-localized with the a4 subunit in the characteristic plasma membrane-enhanced pattern. In human bone, d2 co-localized with the a3 subunit in osteoclasts. This different subunit association in different tissues emphasizes the possibility of the H⁺-ATPase as a future therapeutic target.

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Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673