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Cav1.3 Channels and Sino-Atrial Node Dysfunction

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Pathologies of Calcium Channels

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Abstract

Cardiac pacemaker activity controls the heartbeat in everyday life. The heart impulse originates in the sino-atrial node, which is formed by a small population of myocytes generating automatic action potentials. Automaticity is due to the presence of the slow diastolic depolarization, which leads the membrane voltage at the end of an action potential toward the threshold of the following action potential. The functional role of voltage-dependent Ca2+ channels (VDCCs) to the generation of the slow diastolic depolarization and its regulation by the autonomic nervous system has been matter of debate for almost 30 years. During the last 10 years, however, increasing evidence obtained from genetically modified mice, genomic analysis, and human genetics clearly demonstrated that L-type Cav1.3 channels play a major role in the genesis of cardiac automaticity. First, studies on mice lacking Cav1.3 channels have shown that Cav1.3 loss-of-function leads to bradycardia and atrioventricular conduction block in vivo. Second, patch clamp recordings of pacemaker cells demonstrated that Cav1.3 channels bring critical inward current in a voltage range spanning the diastolic depolarization. Third, genomic analysis demonstrated that Cav1.3 channels are widely expressed in pacemaker tissue of mice, rabbits, and humans. Fourth, two congenital diseases of pacemaking have been attributed to Cav1.3 loss-of-function. In this chapter, we will discuss recent advances in the understanding of the physiological relevance of Cav1.3 channels in cardiac pacemaker activity and review the current knowledge in the involvement of these channels in the determination of heart automaticity and atrioventricular conduction in humans.

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Authors and Affiliations

  1. Département de Physiologie, Universités de Montpellier 1 & 2, CNRS, UMR-5203, Institut de Génomique Fonctionnelle, LabEx ICST, F-34094, Montpellier, France

    Pietro Mesirca & Matteo E. Mangoni

  2. INSERM, U661, F-34094, Montpellier, France

    Pietro Mesirca & Matteo E. Mangoni

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  1. Pietro Mesirca
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  2. Matteo E. Mangoni
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Correspondence to Matteo E. Mangoni .

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  1. Hotchkiss Brain Institute, Department of Physiology and Pharmacology, University of Calgary, Calgary, Canada

    Norbert Weiss

  2. Department of Neurophysiology and Pharmacology, Medical University Vienna, Vienna, Austria

    Alexandra Koschak

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Mesirca, P., Mangoni, M.E. (2014). Cav1.3 Channels and Sino-Atrial Node Dysfunction. In: Weiss, N., Koschak, A. (eds) Pathologies of Calcium Channels. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-40282-1_13

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