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The phosphorylation state of both hERG and KvLQT1 mediates protein-protein interactions between these complementary cardiac potassium channel alpha subunits.

Authors
  • Popescu, Medeea C1
  • Lee, Yeon J1
  • Kim, Stephanie S1
  • Wade, Heidi M1
  • Papakyrikos, Amanda M1
  • Darling, Louise E O2
  • 1 Department of Biological Sciences and Biochemistry Program, Wellesley College, 106 Central St., Wellesley, MA 02481, United States of America. , (United States)
  • 2 Department of Biological Sciences and Biochemistry Program, Wellesley College, 106 Central St., Wellesley, MA 02481, United States of America. Electronic address: [email protected] , (United States)
Type
Published Article
Journal
Biochimica et biophysica acta. Biomembranes
Publication Date
Jan 11, 2021
Volume
1863
Issue
4
Pages
183556–183556
Identifiers
DOI: 10.1016/j.bbamem.2021.183556
PMID: 33444623
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

KvLQT1 and hERG are the α-subunits of the voltage-gated K+ channels which carry the cardiac repolarizing currents IKs and IKr, respectively. These currents function in vivo with some redundancy to maintain appropriate action potential durations (APDs) in cardiomyocytes. As such, protein-protein interactions between hERG and KvLQT1 may be important in normal cardiac electrophysiology, as well as in arrhythmia and sudden cardiac death. Previous phenomenological observations of functional, mutual downregulation between these complementary repolarizing currents in transgenic rabbit models and human cell culture motivate our investigations into protein-protein interactions between hERG and KvLQT1. Previous data suggest that a dynamic, physical interaction between hERG and KvLQT1 modulates the respective currents. However, the mechanism by which hERG-KvLQT1 interactions are regulated is still poorly understood. Phosphorylation is proposed to play a role since modifying the phosphorylation state of each protein has been shown to alter channel kinetics, and both hERG and KvLQT1 are targets of the Ser/Thr protein kinase PKA, activated by elevated intracellular cAMP. In this work, quantitative apFRET analyses of phosphonull and phosphomimetic hERG and KvLQT1 mutants indicate that unphosphorylated hERG does not interact with KvLQT1, suggesting that hERG phosphorylation is important for wild-type proteins to interact. For proteins already potentially interacting, phosphorylation of KvLQT1 appears to be the driving factor abrogating hERG-KvLQT1 interaction. This work increases our knowledge about hERG-KvLQT1 interactions, which may contribute to the efforts to elucidate mechanisms that underlie many types of arrhythmias, and also further characterizes novel protein-protein interactions between two distinct potassium channel families. Copyright © 2021 Elsevier B.V. All rights reserved.

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