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- W2065814614 abstract "The assembly of KCNQ1 with KCNE1 produces the IKSpotassium current that is crucial for the late repolarization of the cardiac action potential. Mutations in either KCNQ1 or KCNE1 genes produce the long QT or short QT syndromes, which are genetically heterogeneous cardiovascular diseases, characterized by ventricular or atrial arrhythmias. The scaffolding A-kinase anchoring protein (AKAP) Yotiao brings together PKA, PP1, PDE4D3, AC9, and the IKS channel complex to achieve regulation following beta adrenergic stimulation. We recently showed that the distal KCNE1 C-terminus interacts with the coiled-coil helix C of KCNQ1 C-terminus. Here we examined the effect of LQT mutations located at this C-terminal interface of the two subunits. Four KCNQ1 LQT mutations located at helix C, S546L, K557E, R555C, and R562M impaired the interaction with KCNE1 C-terminus and produced a drastic reduction in IKS current density mostly caused by a right-shift of the voltage-dependence of channel activation. A much weaker PIP2 binding paralleled the decrease in IKS current density. The KCNE1 LQT mutation, P127T, situated at the distal C-terminus weakened the interaction with KCNQ1 helix C and caused a 40% decrease in IKS current density but with no shift of the voltage-dependence of channel activation. Interestingly, the KCNE1 mutant P127T markedly reduced the cAMP-dependent Yotiao-mediated upregulation of IKS current. While the P127T mutation did not alter the ability of KCNQ1 to interact with Yotiao, it strongly disrupted KCNQ1 phosphorylation of S27, in the presence of Yotiao and cAMP. Similar results were found with a deletion of the distal KCNE1 C-terminus.(del 109-129). These results suggest that the distal KCNE1 C-terminus, probably via its interaction with the coiled-coil helix C, is a crucial determinant for the functional modulation of KCNQ1 by Yotiao-mediated PKA phosphorylation." @default.
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- W2065814614 date "2013-01-01" @default.
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- W2065814614 title "The Distal Kcne1 C-Terminus is Crucial for Yotiao Mediated Pka-Dependent Phosphorylation of KCNQ1" @default.
- W2065814614 doi "https://doi.org/10.1016/j.bpj.2012.11.1186" @default.
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