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The Na+/H+ exchanger NHE1 in stress-induced signal transduction: implications for cell proliferation and cell death

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Abstract

The ubiquitous plasma membrane Na+/H+ exchanger NHE1 is highly conserved across vertebrate species and is extensively characterized as a major membrane transport mechanism in the regulation of cellular pH and volume. In recent years, the understanding of the role of NHE1 in regulating cell function has expanded from one of a household protein involved in ion homeostasis to that of a multifaceted regulator and/or modulator of a wide variety of cell functions. NHE1 plays pivotal roles in response to a number of important physiological stress conditions which, in addition to cell shrinkage and acidification, include hypoxia and mechanical stimuli, such as cell stretch. It has recently become apparent that NHE1-mediated modulation of, e.g., cell migration, morphology, proliferation, and death results not only from NHE1-mediated changes in pHi, cell volume, and/or [Na+]i, but also from direct protein–protein interactions with, e.g., ezrin/radixin/moesin (ERM) proteins and regulation of cellular signaling events, including the activity of mitogen-activated protein kinases (MAPKs) and Akt/protein kinase B (PKB). The aim of this review is to present and discuss new findings implicating NHE1 activation as a central signaling event activated by stress conditions and modulating cell proliferation and death. The pathophysiological importance of NHE1 in modulating the balance between cell proliferation and cell death in cancer and in ischemia/severe hypoxia will also be briefly addressed.

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Acknowledgements

Work on NHE1 in the author’s laboratory is currently supported by the Danish Natural Sciences Research council (Grant no. 21-04-0535), and by grants from the Augustinus Foundation and the Beckett Foundation. Dr. E.K. Hoffmann is gratefully acknowledged for critical reading of the manuscript, and P.M. Cala, M. Rentsch, and B. Darborg for stimulating discussions.

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  1. Department of Biochemistry, August Krogh Building, Institute for Molecular Biology and Physiology, University of Copenhagen, 13, Universitetsparken, Dk-2100, Copenhagen, Denmark

    Stine Falsig Pedersen

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Pedersen, S.F. The Na+/H+ exchanger NHE1 in stress-induced signal transduction: implications for cell proliferation and cell death. Pflugers Arch - Eur J Physiol 452, 249–259 (2006). https://doi.org/10.1007/s00424-006-0044-y

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