Published Online
on June 6, 2005

A more recent version of this article appeared on June 14, 2005

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Submitted on October 27, 2004
Revised on February 15, 2005
Accepted on March 2, 2005

Novel Molecular Mechanism Involving _1D (Cav1.3) L-Type Calcium Channel in Autoimmune-Associated Sinus Bradycardia

Yongxia Qu MD, PhD, Ghayath Baroudi PhD, Yuankun Yue MD, and Mohamed Boutjdir PhD^*

From the Molecular and Cellular Cardiology Program, VA New York Harbor Healthcare System (Y.Q., G.B., Y.Y., M.B.), SUNY Downstate Medical Center (Y.Q., G.B., M.B.), and NYU School of Medicine (M.B.), New York, NY.

^* To whom correspondence should be addressed. E-mail: mohamed.boutjdir{at}med.va.gov.

Background--Congenital heart block (CHB) is an autoimmune disease that affects fetuses/infants born to mothers with anti-Ro/La antibodies (positive IgG). Although the hallmark of CHB is complete atrioventricular block, sinus bradycardia has been reported recently in animal models of CHB. Interestingly, knockout of the neuroendocrine _1D Ca channel in mice results in significant sinus bradycardia and atrioventricular block, a phenotype reminiscent to that seen in CHB. Here, we tested the hypothesis that the _1D Ca channel is a novel target for positive IgG.

Methods and Results--Reverse transcription-polymerase chain reaction, confocal indirect immunostaining, and Western blot data established the expression of the _1D Ca channel in the human fetal heart. The effect of positive IgG on _1D Ca current (I_Ca-L) was characterized in heterologous expression systems (tsA201 cells and Xenopus oocytes) because of the unavailability of _1D-specific modulators. _1D I_Ca-L activated at negative potentials (between -60 and -50 mV). Positive IgG inhibited _1D I_Ca-L in both expression systems. This inhibition was rescued by a Ca channel activator, Bay K8644. No effect on _1D I_Ca-L was observed with negative IgG and denatured positive IgG. Western blot data showed that positive IgG binds directly to _1D Ca channel protein.

Conclusions--The data are the first to demonstrate (1) expression of the _1D Ca channel in human fetal heart, (2) inhibition of _1D I_Ca-L by positive IgG, and (3) direct cross-reactivity of positive IgG with the _1D Ca channel protein. Given that _1D I_Ca-L activates at voltages within the pacemaker’s diastolic depolarization, inhibition of _1D I_Ca-L in part may account for autoimmune-associated sinus bradycardia. In addition, Bay K8644 rescue of _1D I_Ca-L inhibition opens new directions in the development of pharmacotherapeutic approaches in the management of CHB.

Key words: antibodies • sinoatrial node • heart block • ion channels • calcium

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