Na(+)-H+ exchanger subtypes: a predictive review

Abstract

In recent years, many reports have appeared describing distinct heterogeneity of proteins that heretofore were considered to be a single species or type. The division of proteins into different classes or subtypes is aided by pharmacological tools such as selective ligands, functional measurements such as those examining kinetic or regulatory differences, and molecular biological approaches that have identified distinct genes coding for similar yet distinguishable gene products. Currently, much effort is directed toward understanding the significance of these sometimes subtle differences in terms of functional consequences for the cells in which they exist. Although most reports to date involve hormone and neurotransmitter receptor subtypes, it is also possible that other cell surface molecules such as ion transporters exist as multiple subtypes. In this paper we review the current evidence that Na(+)-H+ exchange activity is mediated by different Na(+)-H+ exchanger subtypes. Although subtypes have not been identified with certainty, we can predict certain distinguishing characteristics that these putative subtypes may have that may be of value in correlating predicted gene products obtained from cDNA cloning with previously characterized Na(+)-H+ exchangers.

Regulation of Intracellular pH in Single Rat Cortical Neurons in vitro: A Microspectrofluorometric Study

“…We also recall that the amiloride an alogue MIA similarly exhibited only a partial inhib itory effect. There have recently been other reports on Na + IH + antiporters that are less sensitive to amiloride than expected (Clark and Limbird, 1991;Raley-Susman et aI., 1991;Mellergard et aI., 1992). Our observations may thus be explained by the presence of two (or more) different populations of N a + IH + antiporters, with varying sensitivity to amiloride.…”

Rapid activation of sodium–proton exchange and extracellular signal-regulated protein kinase in fibroblasts by G protein-coupled 5-HT1A receptor involves distinct signalling cascades

“…Because PKC types are frequently implicated in NHE regulation [1,2], we tested their involvement in our model. Figure 2A shows that 1 µM 5-HT further stimulates NHE in the presence of 1 µM PMA.…”

“…Recent studies have shown that multiple stimuli that rapidly activate ERK pathways also rapidly increase NHE activity in many cell types, particularly in fibroblasts. Those stimuli include, but are not limited to : growth factors that modulate tyrosine phosphorylation cycles, integrins, hyperosmotic stress or cell shrinkage, protein kinase C (PKC), tyrosine phosphorylation cascades and heterotrimeric G proteins [1][2][3][4]. Those similarities provide evidence to suggest that ERK may be a direct proximal component of an NHE regulatory pathway [5,6].…”

“…NHEs are expressed at the surface of all mammalian cells, serving to regulate cell volume, intracellular pH, and transepithelial transport of Na + and acid-base equivalents [1,2]. Salient to the current hypothesis are studies showing that microinjection of activated Ras [21] or transfection of the Ha-Ras oncogene [22][23][24] stimulates NHE activity in fibroblasts.…”

New Drugs for the Na + /H + Exchanger. Influence of Na + Concentration and Determination of Inhibition Constants with a Microphysiometer

“…NHE-1 is ubiquitously expressed in mammalian cells (for a review see Clark & Limbird, 1991) and has become a focal point of scientific interest. NHE-1 plays an essential role in the development of hypertension (Feig, D'Occhio & Boylan, 1987;Rosskopf, Fromter & Siffert, 1993;Kuroo, 1995) and cardiac ischaemia (Scholz et al, 1995).…”