Genes in the KCNE family encode single transmembrane domain ancillary subunits that co-assemble with voltage-gated potassium (Kv) channel ␣ 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 ␣ 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 nonacid 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.Voltage-gated potassium (Kv) 2 channels repolarize excitable cells by opening in response to membrane depolarization to permit K ϩ ion efflux. In addition to the 40 known genes that encode the pore-forming (␣) subunits of Kv channels (1), a range of Kv channel ancillary subunits form heteromeric complexes with Kv ␣ subunits to alter their functional properties, thus increasing native Kv current diversity. One family of ancillary subunits, the MinK-related peptides (MiRPs, encoded by KCNE genes), contributes five known members to the human genome. MiRPs are single transmembrane domain subunits that co-assemble with Kv ␣ subunits, altering their gating, conductance, regulation, and pharmacology (2).The MiRP1 protein, encoded by the KCNE2 gene, is now more commonly referred to as KCNE2, and this nomenclature is used here to avoid confusion. KCNE2 regulates hERG potassium channels, and KCNE2-hERG complexes are thought, at least in part, to generate the cardiac I Kr current, the major repolarizing force in human ventricles (3). Mutations in KCNE2 are associated with a form of inherited long QT syndrome, LQT6 (3-5). Further, relatively common polymorphisms in KCNE2 are associated with acquired (drug-induced) long QT syndrome, and some KCNE2 variants increase susceptibility to drug block of the I Kr channel complex (3, 6).Aside from interacting with hERG, KCNE2 has been found to modulate other Kv ␣ subunits in heterologous co-expression studies, including KCNQ1 (also known as Kv7.1) (7), Kv3.1, Kv3.2 (8), and Kv4.2 (9). Effects of KCNE2 on KCNQ1 are particularly dramatic: KCNE2 converts KCNQ1 to a voltage-independent "leak" channel that retains K ϩ selectivity but is constitutively active regardless of membrane ...