The KCNE2 potassium channel ancillary subunit is essential for gastric acid secretion.
Genes in the KCNE family encode single transmembrane domain ancillary subunits that co-assemble with voltage-gated potassium (Kv) channel alpha subunits to alter their function. KCNE2 (also known as MiRP1) is expressed in the heart, is associated with human cardiac arrhythmia, and modulates cardiac Kv alpha subunits hERG and KCNQ1 in vitro. KCNE2 and KCNQ1 are also expressed in parietal cells, leading to speculation they form a native channel complex there. Here, we disrupted the murine kcne2 gene and found that kcne2 (-/-) mice have a severe gastric phenotype with profoundly reduced parietal cell proton secretion, abnormal parietal cell morphology, achlorhydria, hypergastrinemia, and striking gastric glandular hyperplasia arising from an increase in the number of non-acid secretory cells. KCNQ1 exhibited abnormal distribution in gastric glands from kcne2 (-/-) mice, with increased expression in non-acid secretory cells. Parietal cells from kcne2 (+/-) mice exhibited normal architecture but reduced proton secretion, and kcne2 (+/-) mice were hypochlorhydric, indicating a gene-dose effect and a primary defect in gastric acid secretion. These data demonstrate that KCNE2 is essential for gastric acid secretion, the first genetic evidence that a member of the KCNE gene family is required for normal gastrointestinal function.
Roepke
Torsten K
TK
Greenberg Division of Cardiology, Department of Medicine, Cornell University, Weill Medical College, New York, New York 10021, USA.
Anantharam
Arun
A
Kirchhoff
Philipp
P
Busque
Stephanie M
SM
Young
Jeffrey B
JB
Geibel
John P
JP
Lerner
Daniel J
DJ
Abbott
Geoffrey W
GW
D000126:Achlorhydria / Q000235:genetics; D000818:Animals; D002478:Cells, Cultured; D005260:Female; D005744:Gastric Acid / Q000378:metabolism*; D005753:Gastric Mucosa / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D005755:Gastrins / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D018390:Gene Targeting; D006965:Hyperplasia / Q000235:genetics; D006984:Hypertrophy / Q000235:genetics; D051657:KCNQ1 Potassium Channel / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010295:Parietal Cells, Gastric / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D024642:Potassium Channels, Voltage-Gated / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D021122:Protein Subunits / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D013270:Stomach / Q000473:pathology / Q000648:ultrastructure; D015854:Up-Regulation / Q000235:genetics
D005755:Gastrins; D051657:KCNQ1 Potassium Channel; C489620:Kcne2 protein, mouse; C496910:Kcnq1 protein, mouse; D024642:Potassium Channels, Voltage-Gated; D021122:Protein Subunits