Functional cross-talk between phosphorylation and disease-causing mutations in the cardiac sodium channel Na v 1.5

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.