Abstract
Intracellular pH is a fundamental parameter to cell function that requires tight homeostasis. In the absence of any regulation, excessive acidification of the cytosol would have the tendency to produce cellular damage. Mammalian Na+/H+ exchangers (NHEs) are electroneutral Na+-dependent proteins that exchange extracellular Na+ for intracellular H+. To date, there are 9 identified NHE isoforms where NHE1 is the most ubiquitous member, known as the housekeeping exchanger. NHE1 seems to have a protective role in the ischemia-reperfusion injury and other inflammatory diseases. In nociception, NHE1 is found in neurons along nociceptive pathways, and its pharmacological inhibition increases nociceptive behavior in acute pain models at peripheral and central levels. Electrophysiological studies also show that NHE modulates electrical activity of primary nociceptive terminals. However, its role in neuropathic pain still remains controversial. In humans, NHE1 may be responsible for inflammatory bowel diseases since its expression is reduced in Crohn's disease and ulcerative colitis. The purpose of this work is to provide a review of the evidence about participation of NHE1 in the nociceptive processing.
Highlights
Intracellular pH is a fundamental parameter to cell function that requires tight homeostasis [1]
NHE1 seems to have a protective role in the ischemia-reperfusion in ury and other in ammatory diseases
Cells regulate pH through ethxecebsiscaHr+boionnasteto(HfoCrOm3c−a)rbbuoffneicr system which combines acid [5]. en, carbonic with acid is transformed to carbon dioxide (CO2) by the enzyme carbonic anhydrase [5]. e total buffer capacity includes both components [1, 2, 4]. Effective this buffering system has limited capacity to counteract continuous generation of H+ equivalents by metabolism, ongoing transport of ions that alter the pH (H+ and HCO3−), or the presence of diseases that contribute to extracellular acidi cation. e mechanism of regulation of pHi carried out by transporters requires energy as H+ is transported against its electrochemical gradient. us, transporters use the inward Na+ gradient produced by the 3Na+/2K+-ATPase
Summary
Intracellular pH (pHi) is a fundamental parameter to cell function that requires tight homeostasis [1]. Mammalian Na+/H+ exchangers (NHEs) are electroneutral Na+-dependent proteins that exchange extracellular Na+ for intracellular H+ [8,9,10] In animal cells, they are linked to a variety of physiological roles which include regulation of pHi and cell volume [6, 10,11,12,13]. Ere are suggestions that NHEs have a cleaved signal peptide and 11 functional transmembrane spanning domains, an extracellular N-terminus, and an intracellular C-terminus [27]. It could be con rmed by further studies. NHE1 is subject to inhibition. ere is evidence that intracellular acidosis can negatively modulate NHE1 through phosphorylation by protein kinase B (PKB) [53] or dephosphorylation through protein phosphatase 2A (PP2A) [54]. is phosphorylation would interfere with Ca2+-calmodulin binding and could reduce the affinity for intracellular H+
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