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(Circulation Research. 2000;87:903.)
© 2000 American Heart Association, Inc.

Cellular Biology

G_i2 but Not G_i3 Is Required for Muscarinic Inhibition of Contractility and Calcium Currents in Adult Cardiomyocytes

Kohzo Nagata¹, Chianping Ye¹, Mohit Jain, David S. Milstone, Ronglih Liao, Richard M. Mortensen

From the Whitaker Cardiovascular Institute, Cardiac Muscle Research Laboratory (K.N., M.J., R.L.), Boston University School of Medicine, Boston, Mass; Department of Physiology and Medicine (Endocrine) (R.M.M.), University of Michigan Medical School, Ann Arbor, Mich; and Vascular Division, Departments of Pathology (D.S.M) and Medicine (C.Y.), Brigham and Women’s Hospital and Harvard Medical School, Boston, Mass.

Correspondence to Richard M. Mortensen, Department of Physiology and Medicine (Endocrine), University of Michigan Medical School, 7726 Medical Science II, Ann Arbor, MI 48109-0622. E-mail rmort@umich.edu or rliao{at}bu.edu

Abstract—Parasympathetic stimulation of the heart acts through M₂-muscarinic acetylcholine receptors to regulate ion channel activity and subsequent inotropic status. Although muscarinic signal transduction is mediated via pertussis toxin-sensitive G proteins G_i/o, the specific signal transduction requirements of G_i2 and G_i3 in mediating muscarinic regulated L-type calcium currents (I_{Ca, L}), intracellular calcium, and cell contractility remain to be determined. Adult ventricular myocytes were isolated from G_i2-null mice, G_i3-null mice, and their wild-type littermates. Cell shortening, intracellular calcium levels, and I_{Ca, L} were all measured in response to isoproterenol, a ß-adrenergic receptor agonist, and carbachol, a cholinergic receptor agonist. With isoproterenol stimulation, myocytes from all groups demonstrated a marked increase in calcium currents, correlating with augmented intracellular calcium transient amplitude and cell shortening. Carbachol significantly attenuated the isoproterenol response in wild-type and G_i3-null cells but had no effect in G_i2-null cells. This study demonstrates that G_i2, but not G_i3, is required for muscarinic inhibition of the ß-adrenergic response in adult murine ventricular myocytes.

Key Words: Gi proteins • muscarinic receptor • myocyte • contractility • intracellular calcium

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