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Am J Physiol Heart Circ Physiol 294: H979-H985, 2008. First published December 21, 2007; doi:10.1152/ajpheart.00293.2007
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Go controls the hyperpolarization-activated current in embryonic stem cell-derived cardiocytes

Chian P. Ye,1,* Sheng Zhong Duan,2,* David S. Milstone,3 and Richard M. Mortensen2,4

1Division of Endocrinology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts; 2Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan; 3Vascular Research Division, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; and 4Department of Pharmacology and Department of Internal Medicine, Metabolism Endocrine and Diabetes Division, University of Michigan Medical School, Ann Arbor, Michigan

Submitted 8 March 2007 ; accepted in final form 18 December 2007

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.

G proteins; ion channels; nitric oxide; muscarinic receptors


Address for reprint requests and other correspondence: R. M. Mortensen, Depts. of Molecular and Integrative Physiology, 7744 MSII, 1150 W. Med. Ctr. Dr., Ann Arbor, MI 48109-0622 (e-mail: rmort{at}umich.edu)






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