G(o) controls the hyperpolarization-activated current in embryonic stem cell-derived cardiocytes.
Hyperpolarization current (I(f)) is an important player in controlling heart rate and is stimulated by cAMP and inhibited by members of the pertussis toxin-sensitive G-protein G(i)/G(o) family. We have successfully derived cardiocytes from embryonic stem cells lacking G(o) or G(i2) and G(i3). We have established that both basal and isoproterenol-stimulated activities of I(f) in these cardiocytes have typical nodal-atrial characteristics and are unaffected by targeted gene inactivation of the G proteins G(o) or G(i2) and G(i3). Under basal conditions, both G(o) and G(i) are required for muscarinic inhibition of I(f) activity via a mechanism that involves the generation of nitric oxide, whereas, with prior stimulation by beta-agonists, only G(o) is required and G(i) and nitric oxide production are not. Our findings establish an essential role for G(o) in the antiadrenergic effect of muscarinic agent on I(f).
D000200:Action Potentials / Q000502:physiology; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D002217:Carbachol / Q000494:pharmacology; D002460:Cell Line; D016764:Cell Polarity / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D053595:Embryonic Stem Cells / Q000502:physiology*; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000502:physiology*; D007473:Ion Channels / Q000378:metabolism; D007545:Isoproterenol / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D018721:Muscarinic Agonists / Q000494:pharmacology; D032383:Myocytes, Cardiac / Q000502:physiology*; D009569:Nitric Oxide / Q000502:physiology; D018408:Patch-Clamp Techniques; D012849:Sinoatrial Node / Q000166:cytology
D000318:Adrenergic beta-Agonists; D007473:Ion Channels; D018721:Muscarinic Agonists; D009569:Nitric Oxide; D002217:Carbachol; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D007545:Isoproterenol