title: The role of GαO-mediated signaling in the rostral ventrolateral medulla oblongata in cardiovascular reflexes and control of cardiac ventricular excitability.
abstract: The heart is controlled by the sympathetic and parasympathetic limbs of the autonomic nervous system with inhibitory signaling mechanisms recruited in both limbs. The aim of this study was to determine the role of inhibitory heterotrimeric G proteins in the central nervous mechanisms underlying autonomic control of the heart and its potential role in arrhythmogenesis. Mice with conditional deletion of the inhibitory heterotrimeric G protein GαO in the presympathetic area of the rostral ventral lateral medulla (RVLM) were generated to determine the role of GαO-mediated signalling in autonomic control and electrophysiological properties of the heart. GαO deletion within the RVLM was not associated with changes in heart rate (HR) or the arterial blood pressure at rest (home cage, normal behavior). However, exposure to stressful conditions (novel environment, hypoxia, or hypercapnia) in these mice was associated with abnormal HR responses and an increased baroreflex gain when assessed under urethane anesthesia. This was associated with shortening of the ventricular effective refractory period. This phenotype was reversed by systemic beta-adrenoceptor blockade, suggesting that GαO depletion in the RVLM increases central sympathetic drive. The data obtained support the hypothesis that GαO-mediated signaling within the presympathetic circuits of the RVLM contributes to the autonomic control of the heart. GαO deficiency in the RVLM has a significant impact on cardiovascular responses to stress, cardiovascular reflexes and electrical properties of the heart.
authors.affiliation: William Harvey Heart Centre, Barts & The London School of Medicine and Dentistry, London, UK Department of Neuroscience, Physiology and Pharmacology, University College London, London, UK.
authors.forename: Richard
authors.initials: R
authors.lastname: Ang
authors.affiliation: Division of Intramural Research, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina.
authors.forename: Joel
authors.initials: J
authors.lastname: Abramowitz
authors.affiliation: Division of Intramural Research, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina.
authors.forename: Lutz
authors.initials: L
authors.lastname: Birnbaumer
authors.affiliation: William Harvey Heart Centre, Barts & The London School of Medicine and Dentistry, London, UK.
authors.forename: Alexander V
authors.initials: AV
authors.lastname: Gourine
authors.affiliation: Department of Neuroscience, Physiology and Pharmacology, University College London, London, UK a.tinker@qmul.ac.uk.
authors.forename: Andrew
authors.initials: A
authors.lastname: Tinker
mesh_terms: D000818:Animals; D001341:Autonomic Nervous System / Q000502:physiology*; D001794:Blood Pressure; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000235:genetics / Q000502:physiology*; D006321:Heart / Q000502:physiology*; D006339:Heart Rate; D006439:Hemodynamics; D006935:Hypercapnia / Q000503:physiopathology; D000860:Hypoxia / Q000503:physiopathology; D008526:Medulla Oblongata / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D012119:Respiration; D015398:Signal Transduction; D016276:Ventricular Function
chemical_list: C000594262:GNAO1 protein, mouse; D019206:GTP-Binding Protein alpha Subunits, Gi-Go
keywords: Autonomic nervous system; G proteins; blood pressure; cardiac excitability; rostral ventral lateral medulla