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Xin Scaffolding Proteins and Arrhythmias.

Intercalated disc (ICD), a unique specialized structure in cardiac muscle, transmits mechanical force and electrical impulses among cardiomyocytes. Recent studies also suggest that ICD, via scaffolding/anchoring proteins, can spatially organize and maintain key ion channel assemblies required for controlling the cardiac action potential. Defects in these processes can lead to arrhythmias and cardiac sudden death. For example, human Nav1.5 E1053K missense mutation disrupts its binding to ankyrin G, a scaffolding protein required for targeting Nav1.5 to ICD and transverse (T) tubule/lateral membranes of cardiomyocytes. As a consequence, this mutation causes Brugada syndrome [1]. Conversely, ankyrin G-deficient cardiomyocytes show reduced Nav1.5 surface expression and localization as well as reduced INa current density [2]. These findings clearly demonstrate a link between ankyrin G (a scaffolding protein) dysfunction and human arrhythmias. Another scaffolding protein, synapse-associated protein 97 (SAP97), a member of membrane-associated guanylate kinase (MAGUK) family, is preferentially localized to the ICDs and responsible for anchoring the pool of Nav1.5 to the ICDs through its PDZ domain interacting with the 3 last residues (Ser-IleVal) of Nav1.5 [3]. Thus, the question remaining to be addressed is whether the roles of these scaffolding proteins in targeting and maintaining Nav1.5 to the ICD membrane are complementary, cooperative, competitive or redundant.