Infection associated with CIED procedures resulted in substantial incremental admission mortality and long-term mortality that varied with the CIED type and occurred, in part, after discharge. Almost half of the incremental admission cost was for intensive care.

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 ...

Thyroid dysfunction affects 1–4% of the population worldwide, causing defects including neurodevelopmental disorders, dwarfism and cardiac arrhythmia. Here, we show that KCNQ1 and KCNE2 form a TSH-stimulated, constitutively-active, thyrocyte K+ channel required for normal thyroid hormone biosynthesis. Targeted disruption of Kcne2 impaired thyroid iodide accumulation up to 8-fold, impaired maternal milk ejection and halved milk T4 content, causing hypothyroidism, 50% reduced litter size, dwarfism, alopecia, goiter, and cardiac abnormalities including hypertrophy, fibrosis, and reduced fractional shortening. The alopecia, dwarfism and cardiac abnormalities were alleviated by T3/T4 administration to pups, by supplementing dams with T4 pre- and postpartum, or by pre-weaning surrogacy with Kcne2+/+ dams; conversely these symptoms were elicited in Kcne2+/+ pups by surrogacy with Kcne2−/− dams. The data identify a critical thyrocyte K+ channel, provide a possible novel therapeutic avenue for thyroid disorders, and predict an endocrine component to some previously-identified KCNE2- and KCNQ1-linked human cardiac arrhythmias.

Delayed rectifier potassium current diversity and regulation are essential for signal processing and integration in neuronal circuits. Here, we investigated a neuronal role for MinK-related peptides (MiRPs), membrane-spanning modulatory subunits that generate phenotypic diversity in cardiac potassium channels. Native coimmunoprecipitation from rat brain membranes identified two novel potassium channel complexes, MiRP2-Kv2.1 and MiRP2-Kv3.1b. MiRP2 reduces the current density of both channels, slows Kv3.1b activation, and slows both activation and deactivation of Kv2.1. Altering native MiRP2 expression levels by RNAi gene silencing or cDNA transfection toggles the magnitude and kinetics of endogenous delayed rectifier currents in PC12 cells and hippocampal neurons. Computer simulations predict that the slower gating of Kv3.1b in complexes with MiRP2 will broaden action potentials and lower sustainable firing frequency. Thus, MiRP2, unlike other known neuronal beta subunits, provides a mechanism for influence over multiple delayed rectifier potassium currents in mammalian CNS via modulation of alpha subunits from structurally and kinetically distinct subfamilies.

Mutations in human KCNE2, which encodes the MiRP1 potassium channel ancillary subunit, associate with long QT syndrome (LQTS), a defect in ventricular repolarization. The precise cardiac role of MiRP1 remains controversial, in part, because it has marked functional promiscuity in vitro. Here, we disrupted the murine kcne2 gene to define the role of MiRP1 in murine ventricles. kcne2 disruption prolonged ventricular action potential duration (APD), suggestive of reduced repolarization capacity. Accordingly, kcne2 (-/-) ventricles exhibited a 50% reduction in I(K,slow1), generated by Kv1.5--a previously unknown partner for MiRP1. I(to,f), generated by Kv4 alpha subunits, was also diminished, by approximately 25%. Ventricular MiRP1 protein coimmunoprecipitated with native Kv1.5 and Kv4.2 but not Kv1.4 or Kv4.3. Unexpectedly, kcne2 (-/-) ventricular membrane fractions exhibited 50% less mature Kv1.5 protein than wild type, and disruption of Kv1.5 trafficking to the intercalated discs. Consistent with the reduction in ventricular K(+) currents and prolonged ventricular APD, kcne2 deletion lengthened the QT(c) under sevoflurane anesthesia. Thus, targeted disruption of kcne2 has revealed a novel cardiac partner for MiRP1, a novel role for MiRPs in alpha subunit targeting in vivo, and a role for MiRP1 in murine ventricular repolarization with parallels to that proposed for the human heart.