Evolutionary origins of eukaryotic sodium/proton exchangers

Abstract

Brett, Christopher L., Mark Donowitz, and Rajini Rao. Evolutionary origins of eukaryotic sodium/proton exchangers. Am J Physiol Cell Physiol 288: C223-C239, 2005; doi:10.1152/ajpcell.00360.2004.-More than 200 genes annotated as Na ϩ /H ϩ hydrogen exchangers (NHEs) currently reside in bioinformation databases such as GenBank and Pfam. We performed detailed phylogenetic analyses of these NHEs in an effort to better understand their specific functions and physiological roles. This analysis initially required examining the entire monovalent cation proton antiporter (CPA) superfamily that includes the CPA1, CPA2, and NaT-DC families of transporters, each of which has a unique set of bacterial ancestors. We have concluded that there are nine human NHE (or SLC9A) paralogs as well as two previously unknown human CPA2 genes, which we have named HsNHA1 and HsNHA2. The eukaryotic NHE family is composed of five phylogenetically distinct clades that differ in subcellular location, drug sensitivity, cation selectivity, and sequence length. The major subgroups are plasma membrane (recycling and resident) and intracellular (endosomal/TGN, NHE8-like, and plant vacuolar). HsNHE1, the first cloned eukaryotic NHE gene, belongs to the resident plasma membrane clade. The latter is the most recent to emerge, being found exclusively in vertebrates. In contrast, the intracellular clades are ubiquitously distributed and are likely precursors to the plasma membrane NHE. Yeast endosomal ScNHX1 was the first intracellular NHE to be described and is closely related to HsNHE6, HsNHE7, and HsNHE9 in humans. Our results link the appearance of NHE on the plasma membrane of animal cells to the use of the Na ϩ /K ϩ -ATPase to generate the membrane potential. These novel observations have allowed us to use comparative biology to predict physiological roles for the nine human NHE paralogs and to propose appropriate model organisms in which to study the unique properties of each NHE subclass. Naϩ /H ϩ exchanger; NHX; cation proton antiporter; phylogenetic analysis A BASIC PROPERTY OF LIFE is the ability of an organism to regulate cellular pH, volume, and ion composition. The transmembrane exchange of protons for sodium ions (Na ϩ ) is ubiquitous in organisms across all phyla and kingdoms, and underlies fundamental homeostatic mechanisms to control these ions. The family of Na ϩ /H ϩ exchangers (NHEs) plays an important role in diverse physiological processes, including control of cell cycle and cell proliferation (114, 117), transepithelial Na ϩ movement (174), salt tolerance (93, 130), vesicle trafficking, and biogenesis (5, 22). In mammals, NHE dysfunction is associated with pathophysiological conditions that include hypertension, epilepsy, postischemic myocardial arrhythmia, gastric and kidney disease, diarrhea, and glaucoma (36, 106, 174). Drugs such as S8218 and cariporide, which target specific NHE isoforms, are used to reduce the duration of apnea in animal studies and in clinical trials for the prevention of cardiac ischemia-reperfusion injur...

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

“…The CPA superfamily can be divided in three families (CPA1, CPA2, and NaT-DC-Na + -transporting carboxylic acid decarboxylase -) on the basis of their distinct phylogenetic origin 4,5 . Members of this family have between 333 and 900 amino acid residues and exhibit 10 -14 putative transmembrane segments (TMSs).…”

“…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.…”

“…nha-oc/NHA2 is the mouse orthologue of a previously identified human gene HsNHA2 4 . nha-oc/NHA2 belongs to the CPA2 family and based on its similarity to the fungal NHA1, it is likely to be a Na + and K + /H + antiporter 4 .…”

Transport of Na+ and K+ by an antiporter-related subunit from the Escherichia coli NADH dehydrogenase I produced in Saccharomyces cerevisiae

“…The results indicated that the C-terminally truncated NuoL subunit from E. coli complex I exhibited higher sensitivity towards EIPA than the endogenous Na + transporter(s) present in the intracellular vesicles from S. cerevisiae. Na + uptake observed with control vesicles in the absence of ProtA-NuoL N was probably catalyzed by an intracellular Na + /H + exchanger (NHE) like Nhx1 (Brett et al 2005). Under our experimental conditions, EIPA speciWcally inhibited ProtA-NuoL N but not the other Na + transporter(s) present in the ER vesicles, suggesting that amilorides will be useful tools to probe cation transport by complex I subunits in native S. cerevisiae membranes.…”