Diversity of the mammalian sodium/proton exchanger SLC9 gene family

Abstract

Sodium/proton antiporters or exchangers (NHE) are integral membrane proteins present in most, if not all, living organisms. In mammals, these transporters chiefly catalyze the electroneutral exchange of Na(+) and H(+) down their respective concentration gradients and are crucial for numerous physiological processes, ranging from the fine control of intracellular pH and cell volume to systemic electrolyte, acid-base and fluid volume homeostasis. NHE activity also facilitates the progression of other cellular events such as adhesion, migration, and proliferation. Thus far, eight distinct NHE genes (NHE1/SLC9A1-NHE8/SLC9A8) and several pseudogenes have been identified in the human genome. The functional genes encode proteins of varying primary sequence identity (25-70%), but share a common predicted secondary structure comprising 12 conserved membrane-spanning segments at the amino-terminus and a more divergent, cytoplasmically-oriented, carboxy-terminus. They show considerable heterogeneity in their patterns of tissue/cell expression and membrane localization. Functional studies have revealed further differences in their kinetic properties, sensitivity to pharmacological antagonists, and regulation by diverse hormonal and mechanical stimuli. Altered NHE activity has been linked to the pathogenesis of several diseases, including essential hypertension, congenital secretory diarrhea, diabetes, and tissue damage caused by ischemia/reperfusion. Further characterization of their functional properties should lead to a better understanding of their unique contributions to human health and disease.

NHA-oc/NHA2: A mitochondrial cation–proton antiporter selectively expressed in osteoclasts

“…Members of this family share a conserved N-terminus (∼500 amino acids) composed of 10 transmembrane segments, and a short C-terminal tail (∼50-100 amino acids), which appears to be a feature of this subfamily. In fact, all known metazoan NHEs described thus far possess a large (∼130 to ∼450 aa) Cterminus that contain several phosphorylation sites as well as binding sites for regulatory factors, suggesting a regulatory function 6 .…”

“…No eukaryotic member of the CPA2 family, has been characterized 4,6 . On the other hand, many eukaryotic CPA1 members have been identified and characterized, including many Na + /H + exchangers from fungi, plants, and mammals, The Sodium-Proton Exchangers (NHEs), antiporters of the CPA1 family, catalyze Na + and H + antiport.…”

“…Eukaryotic NHEs display a conserved N-terminus consisting of 10 to 12 transmembrane (TM) domains, followed by a less-conserved C-terminal cytoplasmic tail. From a functional standpoint the NHE isoforms differ in their kinetic behavior, sensitivity to inhibitors and regulation by hormonal stimuli 4,6 . NHEs can be ubiquitously expressed or relatively tissue/cell specific.…”

Cell volume regulation in mammalian oocytes and preimplantation embryos

“…In most mammalian cells, the principle inorganic ions involved are Na þ and Cl À , whose transport into the cell is mediated by the coupled activities of Na þ /H þ and Cl À /HCO 3 À exchange (Lang et al, 1998;Wehner et al, 2003;Hoffmann et al, 2009). Upon a decrease in cell volume, Na þ /H þ exchangers (NHEs) of the Slc9 gene family (Alexander and Grinstein, 2006), mainly NHE1, become activated, producing both Na þ influx and an increase in intracellular pH (pH i ) due to H þ efflux (Orlowski and Grinstein, 2004). The increase in pH i then secondarily activates the AE2 HCO 3 À /Cl À exchanger (Humphreys et al, 1995;Jiang et al, 1997) of the anion exchanger (AE) Slc4 family (Romero et al, 2004;Alper, 2006).…”

Molecular cloning, tissue distribution and ontogenetic expression of sodium proton exchanger isoform 2 (NHE-2) mRNA in the small intestine of pigs

“…Na 1 /H 1 exchangers (NHE) are integral membrane proteins present in the plasma membrane of almost all vertebrate cells (Noel and Pouyssgur, 1995;Orlowski and Grinstein, 2004). Under normal physiologic conditions, they mediate an electroneutral exchange of one extracellular Na 1 for an intracellular H 1 that serves to maintain the intracellular pH near 7.1 and cell volume, provide H 1 gradient to transport peptide (Collins et al, 1993).…”