Structural and functional analysis of the Na+/H+ exchanger

Abstract

The mammalian NHE (Na+/H+ exchanger) is a ubiquitously expressed integral membrane protein that regulates intracellular pH by removing a proton in exchange for an extracellular sodium ion. Of the nine known isoforms of the mammalian NHEs, the first isoform discovered (NHE1) is the most thoroughly characterized. NHE1 is involved in numerous physiological processes in mammals, including regulation of intracellular pH, cell-volume control, cytoskeletal organization, heart disease and cancer. NHE comprises two domains: an N-terminal membrane domain that functions to transport ions, and a C-terminal cytoplasmic regulatory domain that regulates the activity and mediates cytoskeletal interactions. Although the exact mechanism of transport by NHE1 remains elusive, recent studies have identified amino acid residues that are important for NHE function. In addition, progress has been made regarding the elucidation of the structure of NHEs. Specifically, the structure of a single TM (transmembrane) segment from NHE1 has been solved, and the high-resolution structure of the bacterial Na+/H+ antiporter NhaA has recently been elucidated. In this review we discuss what is known about both functional and structural aspects of NHE1. We relate the known structural data for NHE1 to the NhaA structure, where TM IV of NHE1 shows surprising structural similarity with TM IV of NhaA, despite little primary sequence similarity. Further experiments that will be required to fully understand the mechanism of transport and regulation of the NHE1 protein are discussed.

NADPH oxidases in lung biology and pathology: Host defense enzymes, and more

“…Original studies of NOX1 gene regulation suggested the presence of a short NOX1 splice variant with intrinsic H + channel activity (8), although this was later realized to be an artifact due to the formation of a stable loop within NOX1 mRNA (6). Intracellular acidification by NOX/DUOX activation may also induce the activation of Na + /H + exchangers (NHE), which are ubiquitously expressed and are critically involved in the regulation of cell volume and shape, and cell adhesion, migration, and proliferation (21,22). Therefore, cellular actions of NOX/DUOX may also include ROSindependent mechanisms.…”

The role of translation elongation factor eEF1A in intracellular alkalinization-induced tumor cell growth

“…[3][4][5] NHE1, the housekeeping isoform of the Na þ /H þ exchanger, is ubiquitously distributed in most tissues and has an important role in the regulation of pH i by exchanging intracellular protons [H þ ] i for extracellular sodium [Na þ ] e . [6][7][8] The transformed cells and tumor cells differ from normal tissues in that they have constitutive NHE1 activity at resting pH i , resulting in an increased pH i . 1,9 Intracellular alkalinization induced by the activation of NHE1 in tumor cells has been shown to play key role in the maintenance and progression of the neoplastic state.…”

Basic structural and functional characteristics of the epidermal barrier in wild mammals living in different habitats and climates

“…Such animals usually have a rather sparse hair coat that increases the danger of epidermal injuries and, thus, includes the necessity of continous barrier repair. In this way, the proliferative properties of NHE-1 are of specific importance (Slepkow et al 2007;Hosogi et al 2009). …”

“…The members of this group of plasma membrane intrinsic proteins are expressed ubiquitously in all tissues, activated by numerous growth factors and implicated in pH homeostasis, cell volume regulation and proliferation, or the adjustment of intracellular pH (e.g. Hachem et al 2003;Slepkow et al 2007;Koliakos et al 2008). In the keratinocytes, NHE-1 is essential for acidifying the lipid microdomains (lipid rafts; Wenneckes et al 2009) and very important for barrier repair or recovery (e.g.…”