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

The cardiac sodium channel Na_V1.5 is an essential modulator of cardiac excitability, with decreased Na_V1.5 levels at the plasma membrane and consequent reduction in sodium current (I_Na) leading to potentially lethal cardiac arrhythmias. Na_V1.5 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_V1.5 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_V1.5 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_V1.5, we here provide an overview of previously demonstrated interactions between Na_V1.5 interacting proteins and +TIPs, which potentially (in)directly impact on Na_V1.5 trafficking. Strikingly, +TIPs interact extensively with several intercalated disc- and lateral membrane-specific Na_V1.5 interacting proteins. Recent work indicates that this interplay of +TIPs and Na_V1.5 interacting proteins mediates the targeted delivery of Na_V1.5 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_V1.5 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.