Submitted on March 8, 2007
Accepted on December 18, 2007
Go controls the hyperpolarization-activated current, If in ES cell-derived cardiocytes
Chian P. Ye1, Sheng Zhong Duan2, David S Milstone3, and Richard M. Mortensen4*
1 Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, United States
2 Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan, United States
3 Pathology, Brigham and Women's Hospital, United States
4 Molecular and Integrative Physiology, Pharmacology and Medicine, University of Michigan, Ann Arbor, Michigan, United States
* To whom correspondence should be addressed. E-mail: rmort{at}umich.edu.
Hyperpolarization current, If, is an important player in controlling heart rate and is stimulated by cAMP and inhibited by members of 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 activity 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 IfIf activity via a mechanism that involves the generation of nitric oxide, whereas with prior stimulation by 
-agonists, only Go is required and neither Gi nor nitric oxide production is. Our findings establish an essential role for Go in the anti-adrenergic effect of muscarinic agent on If.
