The cardiac K+ channel KCNQ1 is essential for gastric acid secretion.
OBJECTIVE
Gastric H+ secretion via the H+/K+-adenosine triphosphatase is coupled to the uptake of K+. However, the molecular identity of luminal K+ channels enabling K+ recycling in parietal cells is unknown. This study was aimed to investigate these luminal K+ channels.


METHODS
Acid secretion was measured in vivo and in vitro; KCNQ1 protein localization was assessed by immunofluorescence, and acid-sensitivity of KCNQ1 by patch-clamp.


RESULTS
We identified KCNQ1, which is mutated in cardiac long QT syndrome, as a K+ channel located in tubulovesicles and apical membrane of parietal cells, where it colocalized with H+/K+-adenosine triphosphatase. Blockade of KCNQ1 current by 293B led to complete inhibition of acid secretion. The putative KCNQ1 subunits, KCNE2 and KCNE3, were abundant in human stomach; KCNE1, however, was absent. Coexpression of KCNE3/KCNQ1 in COS cells led to an acid-insensitive current; KCNE2/KCNQ1 was activated by low extracellular pH.


CONCLUSIONS
We identified KCNQ1 as the missing luminal K+ channel in parietal cells and characterized its crucial role in acid secretion. Because KCNE3 and KCNE2 are expressed in human stomach, one or both are candidates to coassemble with KCNQ1 in parietal cells. Thus, stomach- and subunit-specific inhibitors of KCNQ1 might offer new therapeutical perspectives for peptic ulcer disease.
Grahammer
F
F
Institute of Physiology, Albert-Ludwigs-University, Freiburg, Germany.
Herling
A W
AW
Lang
H J
HJ
Schmitt-Gräff
A
A
Wittekindt
O H
OH
Nitschke
R
R
Bleich
M
M
Barhanin
J
J
Warth
R
R
D000595:Amino Acid Sequence; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D004285:Dogs; D005744:Gastric Acid / Q000378:metabolism*; D005745:Gastric Acidity Determination; D006632:Histamine / Q000494:pharmacology; D006801:Humans; D051656:KCNQ Potassium Channels; D051657:KCNQ1 Potassium Channel; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000032:analysis / Q000502:physiology*; D024642:Potassium Channels, Voltage-Gated; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity
D051656:KCNQ Potassium Channels; D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human; C496910:Kcnq1 protein, mouse; C496911:Kcnq1 protein, rat; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D006632:Histamine