Cardiac ankyrins: Essential components for development and maintenance of excitable membrane domains in heart

Ankyrins are intracellular proteins required for the biogenesis and maintenance of membrane domains in both excitable and non-excitable cells. Ankyrin family polypeptides have been implicated in the targeting and stabilization of membrane proteins including ion channels, transporters, exchangers and cell adhesion molecules in diverse tissues and cell types including the erythrocyte, kidney, lung and brain. Dysfunction in ankyrin-based pathways has previously been linked to abnormalities in vertebrate physiology including spherocytosis and anemia, ataxia and axonal degeneration. Recent findings have illuminated the importance of ankyrin-based pathways in excitable cells of the heart. Specifically, two ankyrin gene products, 220-kDa ankyrin-B and 190-kDa ankyrin-G, have been implicated in the targeting of structurally diverse membrane ion channels and transporters to excitable membrane domains in cardiomyocytes. Moreover, findings in humans and mice have determined the critical nature of ankyrin-based pathways for normal cardiac excitability. Reduction of ankyrin-B expression levels in mice or the presence of ankyrin-B loss-of-function mutations in humans leads to 'ankyrin-B syndrome', a cardiac disease with a spectrum of clinical presentations including bradycardia, ventricular tachycardia and sudden cardiac death in response to catecholaminergic stimuli. Ankyrin-G is required for expression of the major cardiac voltage-gated Na(v) channel, Na(v)1.5, at specialized cardiac membrane domains. Human variants in SCN5A (encodes Na(v)1.5) that block Na(v)1.5 interaction with ankyrin-G lead to loss of Na(v)1.5 membrane expression and Brugada syndrome. Together, these recent findings in heart reinforce the importance of ankyrin-based pathways for normal vertebrate physiology and raise exciting new questions regarding the cellular roles for ankyrin polypeptides in cardiac and other excitable cells. While ankyrins have only been recently identified in heart, our current understanding suggests that elucidating the roles of ankyrins in organizing and targeting protein complexes to excitable membrane domains will yield important insights into the molecular basis of cardiac arrhythmias.