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- W2015019723 abstract "Stimulation of the cardiac K+ channel IKs (KCNQ1/KCNE1) is crucial in mediating the QT shortening at high adrenergic stimulation states, with mutations in the KCNQ1 subunit being linked to a high risk of cardiac events triggered by adrenergic stimulation. In addition to β-adrenergic receptors (AR), α1-AR is also activated upon adrenergic stimulation in the heart. IKs is strongly regulated by β-AR stimulation, but little is known about the role of α1-AR-mediated regulation. In this study, we investigated the molecular mechanism underlying α1-AR-mediated regulation of human IKs channel and mutant channels found in Long QT syndrome type 1 (LQT1). We overexpressed wild-type and mutant KCNQ1/KCNE1 subunits together with the α1A-AR in HEK293T cells. α1-AR activation strongly facilitated voltage dependence of IKs activation independently of β-AR stimulation (V1/2 shift ≅ - 20 mV). This effect was blocked by pretreatment of cell-permeable classic PKC (cPKC) inhibitory peptide and selective cPKC activation by cell-permeable cPKC activator peptide mimicked this effect. A mutation in a putative PKC phosphorylation site in the auxiliary subunit KCNE1 (S102A) specifically abolished the voltage shift by α1-AR stimulation or cPKC activation, suggesting cPKC phosphorylation of KCNE1(S102) increases IKs current through facilitation in voltage dependence of activation. LQT1 associated mutations at the voltage activation domain (S1-S5) of KCNQ1 subunit, also impaired cPKC regulation of the IKs channel independently of β-AR regulation, suggesting that the interactions between the KCNE1 and the voltage-gating domain of KCNQ1 is crucial for cPKC regulation. In conclusion, our study indicates that the voltage activation of IKs by cPKC isoform is important in the IKs channel regulation under adrenergic stimulation and that impairment of this regulation may be linked to LQT1 clinical phenotype." @default.
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- W2015019723 date "2011-02-01" @default.
- W2015019723 modified "2023-09-25" @default.
- W2015019723 title "Activation of KNCQ1/KCNE1 Channel by Classic PKC is Impaired in Long QT Syndrome Type 1" @default.
- W2015019723 doi "https://doi.org/10.1016/j.bpj.2010.12.1293" @default.
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