Go controls the hyperpolarization-activated current in embryonic stem cell-derived cardiocytes

Abstract

Hyperpolarization current ( If) is an important player in controlling heart rate and is stimulated by cAMP and inhibited by members of the pertussis toxin-sensitive G-protein Gi/Go family. We have successfully derived cardiocytes from embryonic stem cells lacking Go or Gi2 and Gi3. We have established that both basal and isoproterenol-stimulated activities of If in these cardiocytes have typical nodal-atrial characteristics and are unaffected by targeted gene inactivation of the G proteins Go or Gi2 and Gi3. Under basal conditions, both Go and Gi are required for muscarinic inhibition of If activity via a mechanism that involves the generation of nitric oxide, whereas, with prior stimulation by β-agonists, only Go is required and Gi and nitric oxide production are not. Our findings establish an essential role for Go in the antiadrenergic effect of muscarinic agent on If.