Na⁺/H⁺Exchangers: Linking Osmotic Dysequilibrium to Modified Cell Function

Abstract

The Na⁺/H⁺ exchangers (NHEs) are among the major ion transporters involved in cell volume regulation. NHE activation leads to a cellular influx of Na⁺ ions and extrusion of H⁺ ions, which are readily replenished from intracellular buffers. This will result in a net import of Na⁺. In many systems NHE operates in parallel to Cl^–-/ HCO3₃^– exchange, resulting in cellular uptake of NaCl. The influx of osmotically obliged water will consequently lead to cell swelling. This makes NHEs suitable to serve as powerful mechanisms for increasing cell volume (CV). The low volume threshold for NHE activation enables the cells to respond to very minute reductions of the CV. By the coupling to the export of H⁺ ions cell volume regulatory NHE activation may lead to changes in intracellular pH. On the other hand NHEs are activated by a broad variety of ligands and by intracellular acidosis, which, in turn, may consequently lead to cell swelling. In addition, NHEs are linked to other intracellular proteins and structures, like e.g. the cytoskeleton, which themelves are involved in the regulation of numerous cellular processes. Therefore NHEs link CV regulation to a diversity of cellular functions, both in physiological and pathophysiological conditions. Six isoforms of the Na⁺/H⁺ exchanger, termed NHE1 - 6, have been cloned so far. NHE 1 - 5 are located in the plasma membrane, whereas NHE6 is sorted to the mitochondrial membrane. NHE1 and NHE6 are the ubiquitously expressed isoforms. The expression of the isoforms NHE2 to NHE5 is restricted to specific tissues and the pattern of their expression, as well as their subcellular localization indicate that they fulfill specialized functions. Cell shrinkage induced activation has been shown for NHE1,2 and 4. In contrast, NHE3 is inhibited by cell shrinkage. In many cells several isoforms are present and assigned to specific membrane domains where they may serve a functional crosstalk between the different ion transporters.

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

“…This activity is essential to control processes such as intracellular pH, cell volume and reuptake of Na + across several epithelia [1][2][3] . It is also involved in other cellular events such as migration, adhesion, proliferation and apoptosis.…”

Identification and subcellular localization of the Na+/H+ exchanger and a novel related protein in the endocrine pancreas and adrenal medulla

“…Sodium-proton exchangers (NHE) are widely distributed integral membrane proteins that regulate cellular volume and pH (Orlowski & Grinstein 1997, Ritter et al 2001. The SLC9 family comprises many pseudogenes and genes that encode at least nine isoforms of the NHE proteins (Orlowski & Grinstein 2004, Nakamura et al 2005.…”

Cell Swelling Stimulates Cytosol to Membrane Transposition of ICln

“…On the other hand, cells have to change their volume to execute specific functions such as cell division, migration, or secretion. Accordingly, cell volume regulatory mechanisms are involved in various cell functions, and disturbances of these mechanisms can lead to severe dysfunctions (1,2).…”

“…The protein is essential for life, because all attempts to genetically knock out ICln in either mice, nematodes, or a cell line failed due to the lethality of the knockout (6). 2 ICln is mainly found to be a water-soluble protein in the cytosol, but some portion is found within or in close association with the cell membrane. Different functions have been discussed for ICln.…”