Novel molecular mechanism involving alpha(1D) (Cav1.3) L-type calcium channel in autoimmune-associated sinus bradycardia

Article

关键词: CONGENITAL HEART-BLOCK;    AMYOTROPHIC-LATERAL-SCLEROSIS;    CARDIAC L-TYPE;    SINOATRIAL NODE;    GENE-EXPRESSION;    CA CHANNELS;    CHILDREN;    MOTHERS;    AUTOANTIBODIES;    ANTIBODIES;   

DOI  :  10.1161/CIRCULATIONAHA.104.517326

来源: SCIE

【 摘 要 】

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 alpha(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 alpha(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 alpha(1D) Ca channel in the human fetal heart. The effect of positive IgG on alpha 1D Ca current ( ICa-L) was characterized in heterologous expression systems ( tsA201 cells and Xenopus oocytes) because of the unavailability of alpha(1D)-specific modulators. alpha(1D) ICa-L activated at negative potentials ( between -60 and -50 mV). Positive IgG inhibited alpha(1D) ICa-L in both expression systems. This inhibition was rescued by a Ca channel activator, Bay K8644. No effect on alpha(1D) ICa-L was observed with negative IgG and denatured positive IgG. Western blot data showed that positive IgG binds directly to alpha(1D) Ca channel protein. Conclusions - The data are the first to demonstrate (1) expression of the alpha(1D) Ca channel in human fetal heart, ( 2) inhibition of alpha(1D) ICa-L by positive IgG, and (3) direct cross-reactivity of positive IgG with the alpha(1D) Ca channel protein. Given that alpha(1D) ICa-L activates at voltages within the pacemaker's diastolic depolarization, inhibition of alpha(1D) ICa-L in part may account for autoimmune-associated sinus bradycardia. In addition, Bay K8644 rescue of alpha 1D ICa-L inhibition opens new directions in the development of pharmacotherapeutic approaches in the management of CHB.

【 授权许可】

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