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Blindness and auditory impairment caused by loss of the sodium bicarbonate cotransporter NBC3

Nature Genetics volume 34, pages 313–319 (2003)Cite this article

Abstract

Normal sensory transduction requires the efficient disposal of acid (H+) generated by neuronal and sensory receptor activity1,2. Multiple highly sensitive transport mechanisms have evolved in prokaryotic and eukaryotic organisms to maintain acidity within strict limits3,4,5. It is currently assumed that the multiplicity of these processes provides a biological robustness6. Here we report that the visual and auditory systems have a specific requirement for H+ disposal mediated by the sodium bicarbonate cotransporter NBC3 (refs. 7,8). Mice lacking NBC3 develop blindness and auditory impairment because of degeneration of sensory receptors in the eye and inner ear as in Usher syndrome9. Our results indicate that in certain sensory organs, in which the requirement to transduce specific environmental signals with speed, sensitivity and reliability is paramount, the choice of the H+ disposal mechanism used is limited.

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Figure 1: Targeted disruption of Slc4a7.
Figure 2: Funduscopic and histologic changes of the retina.
Figure 3: ERGs and single-rod photocurrent responses in Slc4a7−/− mice.
Figure 4: Localization of NBC3 in the mouse retina and apoptosis of photoreceptors in Slc4a7−/− mice.
Figure 5: ABRs and histologic analysis of the cochlea in Slc4a7−/− mice.

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References

  1. Bianchi, L. & Driscoll, M. Protons at the gate: DEG/ENaC ion channels help us feel and remember. Neuron 34, 337–340 (2002).

    Article  CAS  Google Scholar 

  2. Waldmann, R. Proton-gated cation channels—neuronal acid sensors in the central and peripheral nervous system. Adv. Exp. Med. Biol. 502, 293–304 (2001).

    Article  CAS  Google Scholar 

  3. Gross, E. & Kurtz, I. Structural determinants and significance of regulation of electrogenic Na+-HCO3− cotransporter stoichiometry. Am. J. Physiol. Renal Physiol. 283, F876–F887 (2002).

    Article  Google Scholar 

  4. Krulwich, T.A. Alkaliphiles: 'basic' molecular problems of pH tolerance and bioenergetics. Mol. Microbiol. 15, 403–410 (1995).

    Article  CAS  Google Scholar 

  5. Denison, S.H. pH regulation of gene expression in fungi. Fungal Genet. Biol. 29, 61–71 (2000).

    Article  CAS  Google Scholar 

  6. Csete, M.E. & Doyle, J.C. Reverse engineering of biological complexity. Science 295, 1664–1669 (2002).

    Article  CAS  Google Scholar 

  7. Pushkin, A. et al. Cloning, tissue distribution, genomic organization, and functional characterization of NBC3, a new member of the sodium bicarbonate cotransporter family. J. Biol. Chem. 274, 16569–16575 (1999).

    Article  CAS  Google Scholar 

  8. Pushkin, A. et al. Mapping of the human NBC3 (SLC4A7) gene to chromosome 3p22. Genomics 58, 321–322 (1999).

    Article  CAS  Google Scholar 

  9. Kimberling, W.J., Orten, D. & Pieke-Dahl, S. Genetic heterogeneity of Usher syndrome. Adv. Otorhinolaryngol. 56, 11–18 (2000).

    Article  CAS  Google Scholar 

  10. Pittler, S.J. & Baehr, W. Identification of a nonsense mutation in the rod photoreceptor cGMP phosphodiesterase beta-subunit gene of the rd mouse. Proc. Natl. Acad. Sci. USA 88, 8322–8326 (1991).

    Article  CAS  Google Scholar 

  11. Travis, G.H., Groshan, K.R., Lloyd, M. & Bok, D. Complete rescue of photoreceptor dysplasia and degeneration in transgenic retinal degeneration slow (rds) mice. Neuron 9, 113–119 (1992).

    Article  CAS  Google Scholar 

  12. Hao, W. et al. Evidence for two apoptotic pathways in light-induced retinal degeneration. Nat. Genet. 32, 254–260 (2002).

    Article  CAS  Google Scholar 

  13. Krizaj, D. & Copenhagen, D.R. Calcium regulation in photoreceptors. Front. Biosci. 7, 2023–2044 (2002).

    Article  Google Scholar 

  14. Fain, G.L., Matthews, H.R., Cornwall, M.C. & Koutalos, Y. Adaptation in vertebrate photoreceptors. Physiol. Rev. 81, 117–151 (2001).

    Article  CAS  Google Scholar 

  15. Trapp, S., Luckermann, M., Kaila, K. & Ballanyi, K. Acidosis of hippocampal neurones mediated by a plasmalemmal Ca2+/H+ pump. Neuroreport 7, 2000–2004 (1996).

    Article  CAS  Google Scholar 

  16. Krizaj, D., Demarco, S.J., Johnson, J., Strehler, E.E. & Copenhagen, D.R. Cell-specific expression of plasma membrane calcium ATPase isoforms in retinal neurons. J. Comp. Neurol. 451, 1–21 (2002).

    Article  CAS  Google Scholar 

  17. Koulen, P., Fletcher, E.L., Craven, S.E., Bredt, D.S. & Wassle, H. Immunocytochemical localization of the postsynaptic density protein PSD-95 in the mammalian retina. J. Neurosci. 18, 10136–10149 (1998).

    Article  CAS  Google Scholar 

  18. DeMarco, S.J. & Strehler, E.E. Plasma membrane Ca2+-ATPase isoforms 2b and 4b interact promiscuously and selectively with members of the membrane-associated guanylate kinase family of PDZ (PSD95/Dlg/ZO-1) domain-containing proteins. J. Biol. Chem. 276, 21594–21600 (2001).

    Article  CAS  Google Scholar 

  19. Pushkin, A. et al. The COOH termini of NBC3 and the 56-kDa H+-ATPase subunit are PDZ motifs involved in their interaction. Am. J. Physiol. Cell Physiol. 284, C667–C673 (2003).

    Article  CAS  Google Scholar 

  20. Barnes, S., Merchant, V. & Mahmud, F. Modulation of transmission gain by protons at the photoreceptor output synapse. Proc. Natl. Acad. Sci. USA 90, 10081–10085 (1993).

    Article  CAS  Google Scholar 

  21. DeVries, S.H. Exocytosed protons feedback to suppress the Ca2+ current in mammalian cone photoreceptors. Neuron 32, 1107–1117 (2001).

    Article  CAS  Google Scholar 

  22. Spicer, S.S. & Schulte, B.A. Differentiation of inner ear fibrocytes according to their ion transport related activity. Hear. Res. 56, 53–64 (1991).

    Article  CAS  Google Scholar 

  23. Spicer, S.S., Gratton, M.A. & Schulte, B.A. Expression patterns of ion transport enzymes in spiral ligament fibrocytes change in relation to strial atrophy in the aged gerbil cochlea. Hear. Res. 111, 93–102 (1997).

    Article  CAS  Google Scholar 

  24. Salt, A.N. Dynamics of the Inner Ear Fluids. in Physiology of the Ear 333–356 (Singular/Thompson Learning, San Diego, 2001).

    Google Scholar 

  25. Minowa, O. et al. Altered cochlear fibrocytes in a mouse model of DFN3 nonsyndromic deafness. Science 285, 1408–1411 (1999).

    Article  CAS  Google Scholar 

  26. Steel, K.P. & Kros, C.J. A genetic approach to understanding auditory function. Nat. Genet. 27, 143–149 (2001).

    Article  CAS  Google Scholar 

  27. Hmani, M. et al. A novel locus for Usher syndrome type II, USH2B, maps to chromosome 3 at p23–24.2. Eur. J. Hum. Genet. 7, 363–367 (1999).

    Article  CAS  Google Scholar 

  28. Hmani-Aifa, M. et al. Distinctive audiometric features between USH2A and USH2B subtypes of Usher syndrome. J. Med. Genet. 39, 281–283 (2002).

    Article  CAS  Google Scholar 

  29. Pushkin, A. et al. NBC3 expression in rabbit collecting duct: colocalization with vacuolar H+-ATPase. Am. J. Physiol. 277, F974–F981 (1999).

    Article  CAS  Google Scholar 

  30. Pushkin, A., Clark, I., Kwon, T.H., Nielsen, S. & Kurtz, I. Immunolocalization of NBC3 and NHE3 in the rat epididymis: colocalization of NBC3 and the vacuolar H+-ATPase. J. Androl. 21, 708–720 (2000).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank D. Petrasek and S.H. Tsang for their helpful suggestions. This work was supported by grants from the US National Institutes of Health, the Foundation Fighting Blindness, the Factor Family Foundation and the National Kidney Foundation.

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Authors and Affiliations

  1. Department of Neurobiology, Jules Stein Eye Institute and Brain Research Institute, Jules Stein Eye Institute, JDavid Geffen School of Medicine at UCLA, Los Angeles, 90095, California, USA

    Dean Bok

  2. Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, Los Angeles, 90095, California, USA

    Gary Galbraith

  3. Department of Head and Neck Surgery, David Geffen School of Medicine at UCLA, Los Angeles, 90095, California, USA

    Ivan Lopez & Akira Ishiyama

  4. Department of Physiological Sciences, David Geffen School of Medicine at UCLA, Los Angeles, 90095, California, USA

    Michael Woodruff

  5. Department of Ophthalmology, Jules Stein Eye Institute, David Geffen School of Medicine at UCLA, Los Angeles, 90095, California, USA

    Steven Nusinowitz

  6. Lexicon Genetics, The Woodlands, 77381, Texas, USA

    Hector BeltrandelRio, Wenhu Huang, Shulei Zhao, Robert Geske, Charles Montgomery, Isaac Van Sligtenhorst, Carl Friddle, Kenneth Platt & Mary Jean Sparks

  7. Division of Nephrology, Department of Medicine, David Geffen School of Medicine at UCLA, Room 7-155 Factor Building, 10833 Le Conte Avenue, Los Angeles, 90095, California, USA

    Alexander Pushkin, Natalia Abuladze, Ramanath Dukkipati, Weixin Liu & Ira Kurtz

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Correspondence to Ira Kurtz.

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Bok, D., Galbraith, G., Lopez, I. et al. Blindness and auditory impairment caused by loss of the sodium bicarbonate cotransporter NBC3. Nat Genet 34, 313–319 (2003). https://doi.org/10.1038/ng1176

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