title: Pharmacoresistant Cav 2·3 (E-type/R-type) voltage-gated calcium channels influence heart rate dynamics and may contribute to cardiac impulse conduction.
abstract: Voltage-gated Ca(2+) channels regulate cardiac automaticity, rhythmicity and excitation-contraction coupling. Whereas L-type (Cav 1·2, Cav 1·3) and T-type (Cav 3·1, Cav 3·2) channels are widely accepted for their functional relevance in the heart, the role of Cav 2·3 Ca(2+) channels expressing R-type currents remains to be elucidated. We have investigated heart rate dynamics in control and Cav 2·3-deficient mice using implantable electrocardiogram radiotelemetry and pharmacological injection experiments. Autonomic block revealed that the intrinsic heart rate does not differ between both genotypes. Systemic administration of isoproterenol resulted in a significant reduction in interbeat interval in both genotypes. It remained unaffected after administering propranolol in Cav 2·3(-|-) mice. Heart rate from isolated hearts as well as atrioventricular conduction for both genotypes differed significantly. Additionally, we identified and analysed the developmental expression of two splice variants, i.e. Cav 2·3c and Cav 2·3e. Using patch clamp technology, R-type currents could be detected in isolated prenatal cardiomyocytes and be related to R-type Ca(2+) channels. Our results indicate that on the systemic level, the pharmacologically inducible heart rate range and heart rate reserve are impaired in Cav 2·3 (-|-) mice. In addition, experiments on Langendorff perfused hearts elucidate differences in basic properties between both genotypes. Thus, Cav 2·3 does not only contribute to the cardiac autonomous nervous system but also to intrinsic rhythm propagation.
authors.affiliation: Institute of Neurophysiology, University of Köln, Köln, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Galetin
authors.forename: Etienne E
authors.initials: EE
authors.lastname: Tevoufouet
authors.forename: Jakob
authors.initials: J
authors.lastname: Sandmeyer
authors.forename: Jan
authors.initials: J
authors.lastname: Matthes
authors.forename: Filomain
authors.initials: F
authors.lastname: Nguemo
authors.forename: Jürgen
authors.initials: J
authors.lastname: Hescheler
authors.forename: Marco
authors.initials: M
authors.lastname: Weiergräber
authors.forename: Toni
authors.initials: T
authors.lastname: Schneider
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D020908:Calcium Channels, R-Type / Q000172:deficiency / Q000235:genetics*; D002316:Cardiotonic Agents / Q000494:pharmacology; D027682:Cation Transport Proteins / Q000172:deficiency / Q000235:genetics*; D002478:Cells, Cultured; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D006339:Heart Rate / Q000187:drug effects* / Q000502:physiology; D007545:Isoproterenol / Q000494:pharmacology*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009924:Organ Culture Techniques; D018408:Patch-Clamp Techniques; D011433:Propranolol / Q000494:pharmacology*; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D013686:Telemetry
chemical_list: D000889:Anti-Arrhythmia Agents; C498916:Cacna1e protein, mouse; D020908:Calcium Channels, R-Type; D002316:Cardiotonic Agents; D027682:Cation Transport Proteins; D020033:Protein Isoforms; D011433:Propranolol; D007545:Isoproterenol; D002118:Calcium
keywords: E-/R-type Ca2+ channel; ECG; arrhythmia; autonomic nervous system; knockout model