title: Rescuing cardiac automaticity in L-type Cav1.3 channelopathies and beyond.
abstract: Pacemaker activity of the sino-atrial node 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 forecast to double over the next 50 years, with ageing 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 Cav1.3 channels play a major role in the generation and regulation of sino-atrial pacemaker activity and atrioventricular conduction. Mutation in the CACNA1D gene encoding Cav1.3 channels induces loss-of-function in channel activity and underlies the sino-atrial node dysfunction and deafness syndrome (SANDD). Mice lacking Cav1.3 channels (Cav1.3-/-) 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+(IKACh) channels effectively rescues SSS of Cav1.3-/-mice. This new concept of 'compensatory' ion channel targeting shines new light on the principles underlying the pacemaker mechanism and may open the way to new therapies for SSS.
authors.affiliation: Département de Physiologie, Institut de Genomique Fonctionnelle, LabEx ICST, UMR-5203, Centre national de la recherche scientifique, F-34094, Montpellier, France. pietro.mesirca@igf.cnrs.fr.|INSERM U1191, F-34094, Montpellier, France. pietro.mesirca@igf.cnrs.fr.|Université de Montpellier, F-34094, Montpellier, France. pietro.mesirca@igf.cnrs.fr.
authors.forename: Pietro
authors.initials: P
authors.lastname: Mesirca
authors.affiliation: Département de Physiologie, Institut de Genomique Fonctionnelle, LabEx ICST, UMR-5203, Centre national de la recherche scientifique, F-34094, Montpellier, France.|INSERM U1191, F-34094, Montpellier, France.|Université de Montpellier, F-34094, Montpellier, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Bidaud
authors.affiliation: Département de Physiologie, Institut de Genomique Fonctionnelle, LabEx ICST, UMR-5203, Centre national de la recherche scientifique, F-34094, Montpellier, France. matteo.mangoni@igf.cnrs.fr.|INSERM U1191, F-34094, Montpellier, France. matteo.mangoni@igf.cnrs.fr.|Université de Montpellier, F-34094, Montpellier, France. matteo.mangoni@igf.cnrs.fr.
authors.forename: Matteo E
authors.initials: ME
authors.lastname: Mangoni
mesh_terms: D000818:Animals; D001919:Bradycardia / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D020746:Calcium Channels, L-Type / Q000235:genetics / Q000378:metabolism*; D053447:Channelopathies / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D006339:Heart Rate / Q000235:genetics / Q000502:physiology; D006352:Heart Ventricles / Q000378:metabolism* / Q000503:physiopathology; D006801:Humans; D009154:Mutation / Q000235:genetics; D012804:Sick Sinus Syndrome / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D012849:Sinoatrial Node / Q000378:metabolism / Q000503:physiopathology
chemical_list: D020746:Calcium Channels, L-Type
keywords: Cav1.3 channels; Girk4 channels; HCN4 channels; cardiac electrophysiology; pacemaker activity; sick sinus syndrome; sino-atrial node