title: The G-protein-gated K+ channel, IKACh, is required for regulation of pacemaker activity and recovery of resting heart rate after sympathetic stimulation.
abstract: Parasympathetic regulation of sinoatrial node (SAN) pacemaker activity modulates multiple ion channels to temper heart rate. The functional role of the G-protein-activated K(+) current (IKACh) in the control of SAN pacemaking and heart rate is not completely understood. We have investigated the functional consequences of loss of IKACh in cholinergic regulation of pacemaker activity of SAN cells and in heart rate control under physiological situations mimicking the fight or flight response. We used knockout mice with loss of function of the Girk4 (Kir3.4) gene (Girk4(-/-) mice), which codes for an integral subunit of the cardiac IKACh channel. SAN pacemaker cells from Girk4(-/-) mice completely lacked IKACh. Loss of IKACh strongly reduced cholinergic regulation of pacemaker activity of SAN cells and isolated intact hearts. Telemetric recordings of electrocardiograms of freely moving mice showed that heart rate measured over a 24-h recording period was moderately increased (10%) in Girk4(-/-) animals. Although the relative extent of heart rate regulation of Girk4(-/-) mice was similar to that of wild-type animals, recovery of resting heart rate after stress, physical exercise, or pharmacological β-adrenergic stimulation of SAN pacemaking was significantly delayed in Girk4(-/-) animals. We conclude that IKACh plays a critical role in the kinetics of heart rate recovery to resting levels after sympathetic stimulation or after direct β-adrenergic stimulation of pacemaker activity. Our study thus uncovers a novel role for IKACh in SAN physiology and heart rate regulation.
authors.affiliation: Centre National de la Recherche Scientifique UMR 5203, Institut de Génomique Fonctionnelle, Département de Physiologie, Laboratoire d'Excellence Canaux Ioniques d'Intérêt Thérapeutique, 34094 Montpellier, France.
authors.forename: Pietro
authors.initials: P
authors.lastname: Mesirca
authors.forename: Laurine
authors.initials: L
authors.lastname: Marger
authors.forename: Futoshi
authors.initials: F
authors.lastname: Toyoda
authors.forename: Riccardo
authors.initials: R
authors.lastname: Rizzetto
authors.forename: Matthieu
authors.initials: M
authors.lastname: Audoubert
authors.forename: Stefan
authors.initials: S
authors.lastname: Dubel
authors.forename: Angelo G
authors.initials: AG
authors.lastname: Torrente
authors.forename: Mattia L
authors.initials: ML
authors.lastname: Difrancesco
authors.forename: Jana Christina
authors.initials: JC
authors.lastname: Muller
authors.forename: Anne-Laure
authors.initials: AL
authors.lastname: Leoni
authors.forename: Brigitte
authors.initials: B
authors.lastname: Couette
authors.forename: Joël
authors.initials: J
authors.lastname: Nargeot
authors.forename: David E
authors.initials: DE
authors.lastname: Clapham
authors.forename: Kevin
authors.initials: K
authors.lastname: Wickman
authors.forename: Matteo E
authors.initials: ME
authors.lastname: Mangoni
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology*; D000200:Action Potentials; D000818:Animals; D004562:Electrocardiography; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000235:genetics / Q000378:metabolism*; D006339:Heart Rate; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015425:Myocardial Reperfusion; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D005082:Physical Exertion; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D012849:Sinoatrial Node / Q000166:cytology / Q000187:drug effects / Q000294:innervation / Q000502:physiology*; D013312:Stress, Physiological; D013564:Sympathetic Nervous System / Q000502:physiology
chemical_list: D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; C484273:Kcnj5 protein, mouse; D021122:Protein Subunits; D000109:Acetylcholine