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Review
. 2011 Mar 4;108(5):607-18.
doi: 10.1161/CIRCRESAHA.110.224279.

Phenotypical manifestations of mutations in the genes encoding subunits of the cardiac voltage-dependent L-type calcium channel

Carlo Napolitano  1 , Charles Antzelevitch
Affiliations
Review

Phenotypical manifestations of mutations in the genes encoding subunits of the cardiac voltage-dependent L-type calcium channel

Carlo Napolitano et al. Circ Res. .

Abstract

The L-type cardiac calcium channel (LTCC) plays a prominent role in the electric and mechanical function of the heart. Mutations in the LTCC have been associated with a number of inherited cardiac arrhythmia syndromes, including Timothy, Brugada, and early repolarization syndromes. Elucidation of the genetic defects associated with these syndromes has led to a better understanding of molecular and cellular mechanisms and the development of novel therapeutic approaches to dealing with the arrhythmic manifestations. This review provides an overview of the molecular structure and function of the LTCC, the genetic defects in these channels known to contribute to inherited disorders, and the underlying molecular and cellular mechanisms contributing to the development of life-threatening arrhythmias.

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Figures

Figure 1
Figure 1
Schematic of L-type calcium channel. SH3-Src homology domain; GK-guanylate kinase like domain; VWA- von Willebrand factor-A domain
Figure 2
Figure 2
Clinical manifestations of Timothy Syndrome (TS). TS is characterized by multisystem dysfunction and developmental defects causing dysmorphic facial features including round face, flat nasal bridge, receding upper jaw, and thin upper lip (A–C) and webbing of the toes and fingers (syndactyly) (D and E). Electrocardiogram (ECG) shows severe QT interval prolongation causing 2:1 atrioventricular block seen as two atrial beats (P-waves) for each ventricular beat (QRS complex). Right panel ECG shows alternating T-wave polarity (arrows), indicating severe cardiac repolarization abnormality (F). Ventricular tachycardia recorded from a TS patient by an implanted automatic defibrillator (G). (from Splawski et al, Cell:119,19,2004, with permission).
Figure 3
Figure 3
Predicted topology of the Cav1.2 (α1c) subunit with associated β2 and α2δ subunits showing the location of mutations associated with Brugada syndrome (BrS), Brugada syndrome with shorter than normal QTc intervals (BrS+SQTS), early repolarization syndrome (ERS), Timothy Syndrome and idiopathic ventricular fibrillation (IVF) probands. AID = alpha subunit interaction domain; BID=beta subunit interaction domain. SH3-Src homology domain; GK-guanylate kinase like domain. Larger symbols with numbers denote multiple probands with the same mutation. Modified from , with permission. (Illustration Credit: Cosmocyte/Ben Smith).
Figure 4
Figure 4
Cellular basis for electrocardiographic and arrhythmic manifestation of Brugada Syndrome. Each panel shows transmembrane action potentials from one endocardial (top) and two epicardial sites together with a transmural ECG recorded from a canine coronary-perfused right ventricular wedge preparation. A: Control. B: Combined calcium and sodium channel block with terfenadine (5 µM) accentuates the epicardial action potential notch creating a transmural voltage gradient that manifests as a ST segment elevation or exaggerated J wave in the ECG. C: Continued exposure to terfenadine results in all-or-none repolarization at the end of phase 1 at some epicardial sites but not others, creating a local epicardial dispersion of repolarization (EDR) as well as a transmural dispersion of repolarization (TDR). D: Phase 2 reentry occurs when the epicardial action potential dome propagates from a site where it is maintained to regions where it has been lost giving rise to a closely coupled extrasystole. E: Extrastimulus (S1–S2 = 250 msec) applied to epicardium triggers a polymorphic VT. F: Phase 2 reentrant extrasystole triggers a brief episode of polymorphic VT. (From Antzelevitch and Yan , with permission)
Figure 5
Figure 5
Verapamil-induced early repolarization and phase 2 reentry mediated extrasystole. Each panel shows simultaneous recordings from two epicardial and one endocardial site of a canine ventricular coronary-perfused wedge preparation together with a pseudo-ECG recorded across the perfusion bath. A: Control B: Recorded in the presence of 1 µM verapamil. Phase 2 reentry gives rise to a closely coupled extrasystole (Courtesy of Jeffrey Fish, DVM).
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