The Na+/H+ exchanger (NHE) plays a key role in:
Na+/H+ exchanger NHE, SLC9 family with isoforms NHE1 widely expressed in plasma membrane and NHE3 in renal and intestinal brush border, plus organellar NHE6-NHE9, exchanges intracellular H+ for extracellular Na+ with one-to-one stoichiometry electroneutrally. It is primary pH regulatory mechanism alongside bicarbonate transporters and V-ATPase. Upon intracellular acidification after metabolism or proton leak, allosteric H+ sensor accelerates Na+ influx driving H+ extrusion alkalinizing cytoplasm. In kidney proximal tubule NHE3 accounts for majority of Na+ and bicarbonate reabsorption, while in heart NHE1 activated during ischemia contributes to Na+ overload and subsequent Ca2+ accumulation via reverse NCX. NHE also modulates cell volume after shrinkage providing Na+ influx followed by water. Amiloride, cariporide and zoniporide inhibit exchanger used experimentally to dissect pH regulation. Importantly NHE does not regulate intracellular Ca2+ directly, nor flip phospholipids or permit passive Na+ diffusion; its dedicated task is maintenance of cytosolic pH near 7.2 and vectorial Na+ transport in epithelia.
Ref: Orlowski & Grinstein, Pflugers Arch 2004, Na+/H+ exchangers; Wakabayashi et al., Compr Physiol 2013.