Sudden cardiac death remains a leading cause of mortality, with ischemia- and hypoxia-induced arrhythmias as major contributors. The key driver of these arrhythmias is late sodium current (I LATE ) through the voltage-gated sodium channel Nav1.5. In the heart, Nav1.5 channels activate rapidly upon depolarization and undergo near complete inactivation. However, a small residual current (I LATE ) persists after inactivation and plays an integral role in tissue excitability. An increase in the I LATE is responsible for several dysrhythmic complications like long QT syndrome type 3 (LQTS3) and Brugada syndrome. Modulation of Nav channels is nuanced and is performed by several cellular processes and co-factors. One such modulator is the membrane phospholipid PIP 2 (phosphatidylinositol bisphosphate), which is recognized as a master regulator of ion channels. We recently debunked a long-standing belief that Navs did not fall under the PIP 2 umbrella by showing that the skeletal muscle isoform, Nav1.4, is directly regulated by PIP 2 . Physiologically, PIP 2 is hydrolyzed by phospholipase C (PLC) following activation of Gαq-coupled GPCRs. The cardiac milieu has several Gq-coupled receptors that are critical in chronotropic regulation. Here, we show that the cardiac isoform, Nav1.5, is PIP 2 -dependent using Gq signaling through angiotensin in native cells. Using computation and electrophysiology, in tandem, we have identified Nav1.5 variants that expose critical defects in the channel-PIP2 relationship providing rare, structural insight into Nav1.5 channel modulation.
Gada et al. (Sun,) studied this question.