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/DEG family of genes have been found in several human tissues including epithelia and central and peripheral neurons. We describe here the molecular cloning of a cDNA encoding a novel human amiloride-sensitive Na(+) channel subunit that is principally expressed in the small intestine and has been called hINaC (human intestine Na(+) channel). This protein is similar to the recently identified rodent channel BLINaC and is relatively close to the acid sensing ion channels (ASICs) (79 and 29% amino acid identity, respectively). ASICs are activated by extracellular protons and probably participate in sensory neurons to nociception linked to tissue acidosis. hINaC is not activated by lowering the external pH but gain-of-function mutations can be introduced and reveal when expressed in Xenopus oocytes, an important Na(+) channel activity which is blocked by amiloride (IC(50)=0.5 microM). These results suggest the existence of a still unknown physiological activator for hINaC (e.g. an extracellular ligand). The presence of this new amiloride-sensitive Na(+) channel in human small intestine probably has interesting physiological as well as physiopathological implications that remain to be clarified. The large activation of this channel by point mutations may be associated with a degenerin-like behavior as previously observed for channels expressed in nematode mechanosensitive neurons. The hINaC gene has been mapped on the 4q31.3-q32 region of the human genome.
Schaefer
L
L
Institut de Pharmacologie Moléculaire et Cellulaire, CNRS-UPR 411, 660 route des Lucioles, Sophia Antipolis, 06560, Valbonne, France.
Sakai
H
H
Mattei
M
M
Lazdunski
M
M
Lingueglia
E
E
D062565:Acid Sensing Ion Channels; D000584:Amiloride / Q000494:pharmacology*; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002894:Chromosomes, Human, Pair 4 / Q000235:genetics; D003001:Cloning, Molecular; D062626:Degenerin Sodium Channels; D004553:Electric Conductivity; D053503:Epithelial Sodium Channels; D006801:Humans; D006863:Hydrogen-Ion Concentration; D020128:Inhibitory Concentration 50; D007421:Intestine, Small / Q000378:metabolism*; D015640:Ion Channel Gating / Q000187:drug effects*; D007473:Ion Channels / Q000737:chemistry; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000737:chemistry; D009865:Oocytes; D009928:Organ Specificity; D010802:Phylogeny; D020161:Physical Chromosome Mapping; D017354:Point Mutation / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D017386:Sequence Homology, Amino Acid; D026941:Sodium Channel Blockers; D015222:Sodium Channels / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D014982:Xenopus laevis
C568424:ASIC2 protein, human; C407874:ASIC5 protein, human; D062565:Acid Sensing Ion Channels; D062626:Degenerin Sodium Channels; D053503:Epithelial Sodium Channels; D007473:Ion Channels; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D000584:Amiloride