LQT4 gene: the "missing" ankyrin

Abstract

Mutations in ion channels have been implicated in the formation of long QT syndrome (LQTS). However, Mohler et al. have recently uncovered a role for ankyrin-B, a non-ion channel protein, in type IV LQTS. Calcium signalling is altered, and the functions of several channels and pumps that normally interact with wild-type ankyrin-B are impaired in the presence of mutant ankyrin-B. The authors suggest that by disrupting the functions of these channels, a new mechanism has been uncovered that can lead to cardiac myopathy.

Figure 1. Cardiac action potential, electrocardiogram (ECG), and long QT syndrome (LQTS)

A. In LQTS, mutations cause either a gain- or a loss-of-function in I_Na or I_K currents, respectively, that results in prolongation of the cardiac action potential. B. Representative ECG traces in relation to normal atrial and ventricular action potentials. PR and QT intervals, respectively, correspond to the atrial and ventricular activation and repolarization times. Prolongation of the cardiac action potential is reflected as lengthening of the QT interval (blue), an increased vulnerability for the development of early afterdepolarization (EAD), “triggered activity,” and ultimately cardiac arrhythmias [torsade de pointes (TdP) or ventricular fibrillation (VF)]. I_Kr, rapidly activating delayed-rectifier potassium channel current; I_KUR, ultrarapid delayed rectifier potassium current; I_TO, transient outward potassium channel current; I_K1, inward rectifier potassium channel current.

Figure 2. Cardiac ion channel subunits involved in LQTS

Topological maps of the voltage-gated α-subunit for I_Na (SCN5A) and α/β-subunits that make up I_Kr (HERG–KCNE2) and IKs (KCNQ1–KCNE1) are shown in relation to a typical ventricular action potential. Genetic mutations in these subunits are responsible for types 1, 2, 3, 5, and 6 of LQTS.

Figure 3. Candidate mechanisms for intracellular Ca²⁺handling in ventricular myocytes

The proposed mechanisms are as follows: (1) β-adrenergic receptor (β-AR) stimulation, via G_s-mediated activation of adenylate cyclase (AC) and protein kinase A (PKA), phosphorylates phospholamban (PLB) to relieve PLB’s inhibition of the Ca²⁺-ATPase pump (SERCA) and, thereby, to enhance Ca²⁺ uptake by the sarcoplasmic reticulum (SR). (2) Ca²⁺-induced Ca²⁺-release (CICR) through the ryanodine receptor (RyR) is mediated by L-(or T-) type Ca²⁺ channel activation. (3) CICR via activation of voltage-dependent I_Na and the dual roles of the Na+/Ca²⁺ exchanger (NCX). (4) Ankyrin-mediated (blue spheres) localization of ion transport proteins via spectrin binding. (5) Ca²⁺ release triggered by inositol -1,4,5-trisphosphate (IP₃) through IP₃ receptors (IP₃R). (6) Inward rectifying K+ current (I_K1) maintains resting membrane potential and is sensitive to changes in [Ca²⁺]_i homeostasis. (7) CICR triggered by Ca²⁺ entry through tetrodotoxin (TTX)-sensitive Ca²⁺ channel. (8) Ca²⁺ release mediated by “slip mode conductance”, in which PKA-dependent phosphorylation of TTX-sensitive I_Na have altered permeability for Ca²⁺. (9) Ca²⁺-insensitve (I_TO,Ca) and Ca²⁺ -sensitive (I_Cl,Ca) transient outward potassium channels, the latter of which is carried by Cl⁻ rather than K⁺ ions. (10) Reduced Ca²⁺-handling proteins due to a deficiency of ankyrin (blue spheres).

Sandro Yong, PhD, (left) is a Postdoctoral Fellow in the laboratory of Dr. Wang in the Department of Molecular Cardiology, Lerner Research Institute and Center for Cardiovascular Genetics, Department of Cardiovascular Medicine at the Cleveland Clinic Foundation. Qing Wang, PhD, (center) is Associate Staff/Associate Professor of Molecular Genetics, Molecular Cardiology, and Cardiovascular Medicine and Director of Center for Cardiovascular Genetics at the Cleveland Clinic Foundation. QW is supported by NIH grants R01 HL65630 and HL66251, and a Doris Duke Innovation in Clinical Research Award. Please address correspondence to QW. E-mail wangq2@ccf.org; fax 216-444-2682. Xiaoli Tian, PhD, (right) is a Postdoctoral Fellow in the Wang lab Department of Molecular Cardiology, Lerner Research Institute and Center for Cardiovascular Genetics, Department of Cardiovascular Medicine at the Cleveland Clinic Foundation. XL is supported by an American Heart Association Ohio-Valley Postdoctoral Fellowship.