Microtubule plus-end tracking proteins: novel modulators of cardiac sodium channels and arrhythmogenesis

The cardiac sodium channel Na(V)1.5 is an essential modulator of cardiac excitability, with decreased Na(V)1.5 levels at the plasma membrane and consequent reduction in sodium current (I(Na)) leading to potentially lethal cardiac arrhythmias. Na(V)1.5 is distributed in a specific pattern at the plasma membrane of cardiomyocytes, with localization at the crests, grooves, and T-tubules of the lateral membrane and particularly high levels at the intercalated disc region. Na(V)1.5 forms a large macromolecular complex with and is regulated by interacting proteins, some of which are specifically localized at either the lateral membrane or intercalated disc. One of the Na(V)1.5 trafficking routes is via microtubules (MTs), which are regulated by MT plus-end tracking proteins (+TIPs). In our search for mechanisms involved in targeted delivery of Na(V)1.5, we here provide an overview of previously demonstrated interactions between Na(V)1.5 interacting proteins and +TIPs, which potentially (in)directly impact on Na(V)1.5 trafficking. Strikingly, +TIPs interact extensively with several intercalated disc- and lateral membrane-specific Na(V)1.5 interacting proteins. Recent work indicates that this interplay of +TIPs and Na(V)1.5 interacting proteins mediates the targeted delivery of Na(V)1.5 at specific cardiomyocyte subcellular domains, while also being potentially relevant for the trafficking of other ion channels. These observations are especially relevant for diseases associated with loss of Na(V)1.5 specifically at the lateral membrane (such as Duchenne muscular dystrophy), or at the intercalated disc (for example, arrhythmogenic cardiomyopathy), and open up potential avenues for development of new anti-arrhythmic therapies.