Impaired parasympathetic heart rate control in mice with a reduction of functional G protein betagamma-subunits.
Acetylcholine released on parasympathetic stimulation slows heart rate through activation of muscarinic receptors on the sinus nodal cells and subsequent opening of the atrial muscarinic potassium channel (K(ACh)). K(ACh) is directly activated by G protein betagamma-subunits. To elucidate the physiological role of Gbetagamma for the regulation of heart rate and electrophysiological function in vivo, we created transgenic mice with a reduced amount of membrane-bound Gbeta protein by overexpressing nonprenylated Ggamma(2)-subunits in their hearts using the alpha-myosin heavy chain promoter. At baseline and after muscarinic stimulation with carbachol, heart rate and heart rate variability were determined with electrocardiogram telemetry in conscious mice and in vivo intracardiac electrophysiological studies in anesthetized mice. Reduction of the amount of functional Gbetagamma protein by >50% caused a pronounced blunting of the carbachol-induced bradycardia as well as the increases in time- and frequency-domain indexes of heart rate variability and baroreflex sensitivity that were observed in wild types. In addition, sinus node recovery time and inducibility of atrial arrhythmias were reduced in transgenic mice. Our data demonstrate in vivo that Gbetagamma plays a crucial role for parasympathetic heart rate control, sinus node automaticity, and atrial arrhythmia vulnerability.
Gehrmann
Josef
J
Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA.
Meister
Michael
M
Maguire
Colin T
CT
Martins
Donna C
DC
Hammer
Peter E
PE
Neer
Eva J
EJ
Berul
Charles I
CI
Mende
Ulrike
U
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D001145:Arrhythmias, Cardiac / Q000503:physiopathology; D001285:Atropine / Q000494:pharmacology; D002316:Cardiotonic Agents / Q000494:pharmacology; D002462:Cell Membrane / Q000378:metabolism; D005576:Colforsin / Q000494:pharmacology; D003243:Consciousness; D000242:Cyclic AMP / Q000494:pharmacology; D003600:Cytosol / Q000378:metabolism; D004562:Electrocardiography; D004594:Electrophysiology; D015870:Gene Expression / Q000502:physiology; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000494:pharmacology; D006339:Heart Rate / Q000502:physiology*; D020962:Heterotrimeric GTP-Binding Proteins / Q000235:genetics*; D007545:Isoproterenol / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D010275:Parasympathetic Nervous System / Q000187:drug effects / Q000503:physiopathology*; D011433:Propranolol / Q000494:pharmacology; D012849:Sinoatrial Node / Q000502:physiology*; D019076:Transgenes / Q000502:physiology; D014630:Vagus Nerve / Q000503:physiopathology; D014665:Vasodilator Agents / Q000494:pharmacology
D000889:Anti-Arrhythmia Agents; D002316:Cardiotonic Agents; D014665:Vasodilator Agents; D005576:Colforsin; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D001285:Atropine; D011433:Propranolol; D000242:Cyclic AMP; D020962:Heterotrimeric GTP-Binding Proteins; D007545:Isoproterenol