Defects in Ankyrin-Based Protein Targeting Pathways in Human Arrhythmia

Ion channels and transporters regulate transmembrane electrochemical gradients to control cardiomyocyte depolarization/repolarization and cell excitability. Importantly, ion channel and transporter function depends on proper expression and localization within specific cellular membrane domains. Ankyrins are a family of proteins that are widely expressed in vertebrate tissues including heart. Recently, ankyrin-based cellular pathways have been identified as critical for normal ion channel and transporter membrane targeting in ventricular cardiomyocytes and sinoatrial node cells. Moreover, findings in both mice and humans implicate dysfunction in ankyrin-based pathways in excitable cell disease including potentially fatal ventricular arrhythmias and sinus node disease. Specifically, human ANK2 loss-of-function mutations may result in “ankyrin-B-syndrome” (previously called type 4 long QT syndrome). In fact, ankyrin-B syndrome represents a new class of arrhythmia distinct from typical long QT syndromes, notably in its characteristic representing sick sinus syndrome with bradycardia and risk of sudden death. In addition to ANK2-associated cardiac disease, dysfunction in the related ankyrin-G-based cellular pathway for voltage-gated Nav channel targeting has also been implicated in human arrhythmia, notably the Brugada syndrome. This chapter will focus on the cell biology of cardiac ankyrins in human arrhythmias.