Open AccessFunctional cross-talk between phosphorylation and disease-causing mutations in the cardiac sodium channel Na v 1.5
Author(s) -
Iacopo Galleano,
Hendrik Harms,
Koushik Choudhury,
Keith K. Khoo,
Lucie Delemotte,
Stephan A. Pless
Publication year - 2021
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.2025320118
Subject(s) - phosphorylation , sodium channel , mutation , biology , microbiology and biotechnology , nav1.5 , mutant , gating , biochemistry , chemistry , biophysics , sodium , gene , organic chemistry
Significance The cardiac sodium channel (Na v 1.5) is crucial for generating a regular heartbeat. It is thus not surprising that Na v 1.5 mutations have been linked to life-threatening arrhythmias. Interestingly, Na v 1.5 activity can also be altered by posttranslational modifications, such as tyrosine phosphorylation. Our combination of protein engineering and molecular modeling has revealed that the detrimental effect of a long QT3 patient mutation is only exposed when a proximal tyrosine is phosphorylated. This suggests a dynamic cross-talk between the genetic mutation and a neighboring phosphorylation, a phenomenon that could be important in other classes of proteins. Additionally, we show that phosphorylation can affect the channel’s sensitivity toward clinically relevant drugs, a finding that may prove important when devising patient-specific treatment plans.