Distinct CASK domains control cardiac sodium channel membrane expression and focal adhesion anchoring

Abstract

Membrane-associated guanylate kinase (MAGUK) proteins function as adaptor proteins to mediate the recruitment and scaffolding of ion channels in the plasma membrane in various cell types. In the heart, the protein CASK (Calcium/CAlmodulin-dependent Serine protein Kinase) negatively regulates the main cardiac sodium channel, NaV1.5, which carries the sodium current (INa) by preventing its anterograde trafficking. CASK is also a new member of the dystrophin-glycoprotein complex, and like syntrophin, binds to the C-terminal domain of the channel. Here we show that both L27B and GUK domains are required for the negative regulatory effect of CASK on INa and NaV1.5 surface expression and that the HOOK domain is essential for interaction with the cell adhesion dystrophin-glycoprotein complex. Thus, the multi-modular structure of CASK potentially provides the ability to control channel delivery at adhesion points in cardiomyocyte.\n\nSUMMARYSequential functional domain deletion approach identifies three critical domains of CASK in cardiomyocytes. CASK binds the cell adhesion dystrophin-glycoprotein complex through HOOK domain and inhibits NaV1.5 channel membrane expression by impeding trafficking through L27B and GUK domains.