Rescuing cardiac automaticity in L-type Cav1.3 channelopathies and beyond

Abstract

Pacemaker activity of the sino-atrial generates the heart rate. Disease of the sinus node and impairment of atrioventricular conduction induce an excessively low ventricular rate (bradycardia), which cannot meet the needs of the organism. Bradycardia accounts for about half of the total workload of clinical cardiologists. The "sick sinus" syndrome (SSS) is characterized by sinus bradycardia and periods of intermittent atrial fibrillation. Several genetic or acquired risk factors or pathologies can lead to SSS. Implantation of an electronic pacemaker constitutes the only available therapy for SSS. The incidence of SSS is forecasted to double over the next 50 years, with aging of the general population thus urging the development of complementary or alternative therapeutic strategies. In recent years an increasing number of mutations affecting ion channels involved in sino-atrial automaticity have been reported to underlie inheritable SSS. L-type Ca_v1.3 channels play a major role in the generation and regulation of sino-atrial pacemaker activity and atrioventricular conduction. Mutation in the CACNA1D gene encoding Ca_v1.3 channels induces loss-of-function in channel activity and underlies the Sino-Atrial Node Dysfunction and Deafness syndrome (SANDD). Mice lacking Ca_v1.3 channels (Ca_v1.3^−/−) fairly recapitulate SSS and constitute a precious model to test new therapeutic approaches to handle this disease. Work in our laboratory shows that targeting G protein gated K⁺ (I_KACh) channels effectively rescues SSS of Ca_v1.3^−/− mice. This new concept of "compensatory" ion channel targeting shines new light in the principles underlying the pacemaker mechanism and may open the way to new therapies of SSS.

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