title: The in vivo regulation of heart rate in the murine sinoatrial node by stimulatory and inhibitory heterotrimeric G proteins.
abstract: Reciprocal physiological modulation of heart rate is controlled by the sympathetic and parasympathetic systems acting on the sinoatrial (SA) node. However, there is little direct in vivo work examining the role of stimulatory and inhibitory G protein signaling in the SA node. Thus, we designed a study to examine the role of the stimulatory (Gαs) and inhibitory G protein (Gαi2) in in vivo heart rate regulation in the SA node in the mouse. We studied mice with conditional deletion of Gαs and Gαi2 in the conduction system using cre-loxP technology. We crossed mice in which cre recombinase expression was driven by a tamoxifen-inducible conduction system-specific construct with "Gαs floxed" and "Gαi2 floxed" mice. We studied the heart rate responses of adult mice compared with littermate controls by using radiotelemetry before and after administration of tamoxifen. The mice with conditional deletion of Gαs and Gαi2 had a loss of diurnal variation and were bradycardic or tachycardic, respectively, in the daytime. In mice with conditional deletion of Gαs, there was a selective loss of low-frequency power, while with deletion of Gαi2, there was a loss of high-frequency power in power spectral analysis of heart rate variability. There was no evidence of pathological arrhythmia. Pharmacological modulation of heart rate by isoprenaline was impaired in the Gαs mice, but a muscarinic agonist was still able to slow the heart rate in Gαi2 mice. We conclude that Gαs- and Gαi2-mediated signaling in the sinoatrial node is important in the reciprocal regulation of heart rate through the autonomic nervous system.
authors.affiliation: William Harvey Heart Centre, Barts and The London School of Medicine and Dentistry, London, United Kingdom;
authors.forename: Sonia
authors.initials: S
authors.lastname: Sebastian
authors.forename: Richard
authors.initials: R
authors.lastname: Ang
authors.forename: Joel
authors.initials: J
authors.lastname: Abramowitz
authors.forename: Lee S
authors.initials: LS
authors.lastname: Weinstein
authors.forename: Min
authors.initials: M
authors.lastname: Chen
authors.forename: Andreas
authors.initials: A
authors.lastname: Ludwig
authors.forename: Lutz
authors.initials: L
authors.lastname: Birnbaumer
authors.forename: Andrew
authors.initials: A
authors.lastname: Tinker
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D001341:Autonomic Nervous System / Q000378:metabolism / Q000503:physiopathology; D001919:Bradycardia / Q000378:metabolism / Q000503:physiopathology; D002864:Chromogranins; D002940:Circadian Rhythm; D015716:Electrocardiography, Ambulatory / Q000379:methods; D051960:GTP-Binding Protein alpha Subunit, Gi2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D006339:Heart Rate / Q000187:drug effects; D019426:Integrases / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018721:Muscarinic Agonists / Q000494:pharmacology; D015398:Signal Transduction; D012849:Sinoatrial Node / Q000187:drug effects / Q000294:innervation / Q000378:metabolism* / Q000503:physiopathology; D013610:Tachycardia / Q000378:metabolism / Q000503:physiopathology; D013686:Telemetry; D013997:Time Factors
chemical_list: D000318:Adrenergic beta-Agonists; D002864:Chromogranins; D018721:Muscarinic Agonists; C045073:Cre recombinase; D019426:Integrases; C498642:Gnas protein, mouse; D051960:GTP-Binding Protein alpha Subunit, Gi2; D019205:GTP-Binding Protein alpha Subunits, Gs; C498016:Gnai2 protein, mouse
keywords: G protein; heart rate; sinoatrial node