Targeted deletion of kcne2 impairs ventricular repolarization via disruption of I _K,slow1 and I _to,f

Abstract

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.

Prenatal androgen exposure causes hypertension and gut microbiota dysbiosis

“…106 , 107 Androgens may promote the development of cardiomyopathy by upregulating potassium channel regulatory subunits and reducing cardiomyocyte repolarization. 108 , 109 Indeed, the enlarged walls and decreased cross-sectional area of the left ventricle in the PNA animals resembles early-stage concentric cardiac hypertrophy, although mRNA expression of markers of cardiac hypertrophy were unchanged in PNA animals. Support for this possibility is provided by previous studies in which antiandrogenic treatment attenuated cardiac hypertrophy.…”

KCNE2 and the K+channel

“…This will be discussed in detail in the following sections, but essentially KCNE2 ensures apical trafficking of the KCNQ1 a subunit in some polarized epithelial cell types in vivo, 17,18 while in mouse ventricular cardiomyocytes KCNE2 is required for the Kv1.5 (KCNA5) a subunit to target to the intercalated discs. 19 When KCNE2-a complexes reach the plasma membrane, they typically exhibit functional properties different to those of channels formed by a subunits in the absence of KCNE2. KCNE2 can alter the unitary conduction, activation, inactivation, deactivation, responses to pH, regulation by other proteins, and pharmacology of its a subunit partners-sometimes spectacularly so (for detailed review, see ref.…”

“…12,83 While the weight of evidence, including studies of human, canine, guinea-pig and rat heart, suggests a role for KCNE2 in regulating I Kr in vivo, 12,28,65,67,85 this association is not universally agreed upon, 80 and the cardiac function of KCNE2 is certainly not as simple as this. Kcne2 deletion delays ventricular repolarization in adult mice, 19 in which mERG and I Kr are essentially absent from ventricular myocytes.…”

“…19 Kcne2 deletion in mice reduces ventricular Kv1.5 current (I Kur ) density 2-fold, by an unknown mechanism that may be related to inability of Kv1.5 to target to the intercalated discs in the absence of KCNE2 19 Figure 3. KCNE2 in ventricular myocytes.…”

“…KCNE2 reduces Kv2.1 current density and slows its activation, and LQTS-associated KCNE2 mutations exaggerate these effects, 67 but a role for Kv2.1 in human heart has yet to be established, and the KCNE2-Kv2.1 association was not observed in mouse ventricles. 19 Finally, KCNE2 alters function of the hyperpolarization activated, cyclic nucleotide-gated, monovalent cation nonspecific channels (HCN1, 2 and 4), also known as pacemaker channels, in vitro and may also do so in mammalian heart. 65 HCN2 expresses both a time-and voltage-dependent, hyperpolarization-activated current (I h ) and an instantaneous current (I inst(HCN2) ); KCNE2 was found to decrease (I h ) but increase I inst(HCN2) when co-expressed with mouse HCN2.…”