Molecular cloning, functional expression and chromosomal localization of an amiloride-sensitive Na+ channel from human small intestine

Amiloride-sensitive Na+ channels belonging to the recently discovered NaC/D EG family of genes have been found in several human tissues including epith elia and central and peripheral neurons, We describe here the molecular clo ning of a cDNA encoding a nor cl human amiloride-sensitive Na+ channel subu nit that is principally expressed in the small intestine and has been calle d hINaC (human intestine Na+ channel), This protein is similar to the recen tly identified rodent channel BLINaC and is relatively close to the acid se nsing ion channels (ASICs) (79 and 29%, amino acid identity, respectively). ASICs are activated by extracellular protons and probably participate in s ensory neurons to nociception linked to tissue acidosis, hINaC is not activ ated by lowering the external pll but gain-of-function mutations call he in troduced and reveal when expressed in Xenopus oocytes, an important Na+ cha nnel activity which is blocked by amiloride (IC50 = 0.5 mu M). These result s suggest the existence of a still unknown physiological activator for hINa C (e.g. an extracelluar ligand), The presence of this new amiloride-sensiti ve Na+ channel in human small intestine probably has interesting physiologi cal as well as physiopathological implications that remain to he clarified. The large activation of this channel by point mutations may be associated, vith a degenerin-like behavior as previously observed for channels expresse d in nematode mechanosensitive neurons. The hINaC gene has been mapped on t he 4q31.3-q32 region of the human genome, (C) 2000 Federation of European B iochemical Societies.