Defining a new paradigm for human arrhythmia syndromes: phenotypic manifestations of gene mutations in ion channel- and transporter-associated proteins

Abstract

Over the past 15 years, gene mutations in cardiac ion channels have been linked to a host of potentially fatal human arrhythmias including long QT syndrome, short QT syndrome, Brugada syndrome, and catecholaminergic polymorphic ventricular tachycardia. More recently, a new paradigm for human arrhythmia has emerged based on gene mutations that affect the activity of cardiac ion channel- and transporter- associated proteins. As part of the Circulation Research thematic series on inherited arrhythmias, this review focuses on the emerging field of human arrhythmias caused by dysfunction in cytosolic gene products (including ankyrins, yotiao, syntrophin, and caveolin-3) that regulate the activities of key membrane ion channels and transporters.

Figure 1. Ankyrin-B organizes membrane ion channels and transporters in ventricular cardiomyocytes

Model depicts multifunctional role for ankyrin-B in targeting and clustering Na/Ca exchanger, Na/K ATPase, and IP3 receptor at transverse-tubule/sarcoplasmic reticulum domains in ventricular cardiomyocytes. Ankyrin-B also organizes structural (obscurin, betaII spectrin) and signaling (protein phosphatase 2A) in myocytes.

Figure 2. Cardiac voltage-gated sodium channel macromolecular complex

Model illustrates cardiac voltage-gated sodium channel alpha (Nav1.5, black) and beta (white) subunits, as well as associated complex members including ankyrin-G, alpha1 syntrophin, nNOS, and PMCA4b. Nav1.5 is also associated with caveolin-3 although the mechanism for the interaction is still unclear.

Figure 3. Cardiac IKs and IKr complexes in heart

In addition to interactions of channel alpha and beta subunits for both complexes, the Kv7.1 alpha subunit encoded by KCNQ1 also associates with yotiao (AKAP9) in heart which recruits signaling molecules protein phosphatase 1 (PP1), protein kinase A (PKA), and phosphodiesterase 4D3 (PDE4D3) to the IKs complex. In brain, yotiao also associates with specific isoforms of adenylyl cyclase (AC).