Review articleCardiac ankyrins in health and disease
Introduction
Ankyrin polypeptides, once thought to solely serve structural roles in the erythrocyte, are now recognized as multifunctional proteins involved in targeting and stabilization of ion channels and transporters in diverse tissues and cell types including skeletal and cardiac myocytes, neurons, photoreceptors, and epithelial cells [1], [2], [3], [4]. Ankyrin-R (ANK1 gene) was originally identified in the late 1970s as a critical structural protein of the erythrocyte plasma membrane [5]. In the mid 1990s, human gene mutations in ANK1 were discovered to cause erythrocyte spectrin-deficiency, resulting in hereditary spherocytosis and anemia [6]. Over the past decade, advances in ankyrin biology have generated new insights into the molecular mechanisms underlying a diverse range of human cardiovascular disorders. Ankyrin-B and ankyrin-G are now recognized to play essential roles in the targeting and membrane stabilization of ion channels and transporters in cardiomyocytes [7], [8], [9], [10], [11], [12], [13], [14], [15], [16]. Inherited loss-of-function variants in the ankyrin-B gene (ANK2) cause “ankyrin-B syndrome” ventricular arrhythmias [10]. Moreover, ankyrin-B dysfunction was recently linked with human sinus node disease [17]. Ankyrin-G, a second ankyrin gene product, is required for targeting and membrane regulation of the primary voltage-gated sodium channel (Nav1.5) in human heart [12], [16]. A human mutation in the Nav1.5 ankyrin-G-binding motif is associated with Brugada syndrome, an arrhythmia syndrome associated with risk of sudden death [12]. Thus, the identification of genetic variants in ankyrins and associated proteins (e.g. Nav1.5) has provided new information on the cellular and molecular basis of cardiac arrhythmias. This review will primarily focus on the emerging roles of ankyrin-B and ankyrin-G in cardiac function and cardiovascular disease.
Section snippets
Ankyrin genes
Ankyrin genes ANK1 (human chromosome 8p11), ANK2 (human chromosome 4q25–27), and ANK3 (human chromosome 10q21) encode three canonical ankyrins: 210 kD ankyrin-R, 220 kD ankyrin-B, and 190 kD ankyrin-G, respectively [4], [18]. Ankyrin-R expression is restricted to erythrocytes, neurons, and skeletal muscle, whereas ankyrin-B and ankyrin-G are ubiquitously expressed [4], [18]. In addition to canonical ankyrins, alternative splicing of ankyrin genes produces a series of gene products with distinct
Structure and function of ankyrin polypeptides
Canonical ankyrins consist of four major domains: a membrane-binding domain (MBD), a spectrin-binding domain (SBD), a death domain (DD), and a C-terminal domain (CTD, Fig. 1) [29]. The ankyrin membrane-binding domain (24 ANK repeats) interacts with a host of diverse membrane proteins, with each ankyrin polypeptide linked to a unique set of associated proteins (Table 1). Specifically, the ankyrin MBD interacts with ion channels, transporters, and pumps including the Na/K ATPase, voltage-gated Na+
Ankyrin-B syndrome
The importance of ankyrins for normal heart physiology is highlighted by the growing number of cardiac arrhythmia syndromes linked to ankyrin dysfunction. An early example may be found in the long QT (LQT) syndrome, a heterogenous group of inherited arrhythmogenic diseases characterized by prolonged corrected QT interval (QTc) on the electrocardiogram (ECG) and susceptibility to life-threatening arrhythmias [53], [54]. To date, nearly a dozen LQT syndromes have been identified. However,
Ankyrin-B is essential for sinoatrial node automaticity
While early studies focused on the role of ankyrin-B in ventricular cardiomyocytes and arrhythmias, it is now clear that ankyrin-B is expressed throughout the heart. In fact, recent studies have identified an important role for ankyrin-B in sinoatrial node pacemaking. Sinus node dysfunction (SND), or “sick sinus syndrome” is considered a disease of the elderly with an exponential increase in its frequency with age [64], [65]. In fact, SND affects one in every 600 individuals over age 65 years
Ankyrin-B and obscurin target cardiac protein phosphatase 2A
Ankyrin-B plays a critical role in cardiomyocyte signaling pathways. Specifically, ankyrin-B was recently identified as a binding partner in ventricular myocytes for B56α, the regulatory subunit of protein phosphatase 2A (PP2A) [14]. PP2A is a multifunctional serine/threonine phosphatase linked with cardiac β-adrenergic signaling [71], [72], [73]. Furthermore, PP2A regulates a number of ion channels and transporters including L-type Ca2+-channels [71], [74], ryanodine receptor [75], IP3
Ankyrin-B in acquired arrhythmias
Recent large animal studies suggest that ankyrin-B dysfunction is associated with common acquired forms of heart disease [81]. Electrical remodeling in the peri-infarct zone creates a substrate favorable to the initiation and maintenance of reentrant arrhythmias following myocardial infarction [82], [83]. An important component of this remodeling process involves the redistribution of ion channels in surviving myocytes near the infarct [84], [85]. Recently, ankyrin-B levels were shown to be
Common genetic variants in ANK2 are associated with QT interval variability
Recent data from large human population studies have raised the exciting prospect that variability in ankyrin-B function may influence arrhythmia susceptibility in the general human population. Prolongation of QT interval causes susceptibility to polymorphic ventricular tachycardia and sudden death [86], [87]. Conversely, shortening of QT interval may facilitate life-threatening reentrant arrhythmias in vulnerable patients [88]. In the general population, the QT interval is distributed
Ankyrin-G is required for targeting of cardiac Nav1.5
Voltage-gated sodium channels (Nav) are required for normal vertebrate cardiac function. Dysfunction in cardiac Nav1.5 may result in type 3 long QT syndrome, conduction defects, sick sinus syndrome, and Brugada syndrome [90], [95], [96], [97]. While the mechanisms underlying Nav1.5 channel biophysics are well described, little is known regarding the pathways required for targeting and regulation of Nav1.5 at cardiac membrane domains.
In the nervous system, ankyrin-G is required for Nav channel
Dysfunction in the ankyrin-G-based Nav1.5 channel targeting pathway is associated with human Brugada syndrome
The Brugada syndrome is an autosomal-dominant, potentially-fatal cardiac arrhythmia syndrome characterized by ST segment elevation in the precordial leads associated with right bundle branch block and T-wave inversion [109]. In affected individuals, sudden death is most prevalent at night, and is the result of ventricular fibrillation [110], [111]. Gene variants in SCN5A (encodes Nav1.5) account for up to ∼ 30% of Brugada syndrome cases [112], and are associated with Nav1.5 biophysical defects
Summary
Exciting discoveries over the past decade have established the importance of local signaling domains for excitable cell function. While key myocyte membrane receptors, transporters, and ion channels remain the primary mediators of cardiomyocyte signaling, the proteins responsible for local organization of ion channels and transporters with signaling and effector proteins are now recognized as critical determinants of normal myocyte function. Over the past 5 years, ankyrin-B and ankyrin-G have
Acknowledgments
We acknowledge financial support from the NIH (HL084583 and HL083422 to PJM; T32 HL07121 (PI: Abboud) to SMH); the Pew Scholars Trust (PJM), and the American Heart Association (0930378N to TJH).
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