Gα i2 but Not Gα i3 Is Required for Muscarinic Inhibition of Contractility and Calcium Currents in Adult Cardiomyocytes

Abstract

Abstract —Parasympathetic stimulation of the heart acts through M 2 -muscarinic acetylcholine receptors to regulate ion channel activity and subsequent inotropic status. Although muscarinic signal transduction is mediated via pertussis toxin-sensitive G proteins Gα i/o , the specific signal transduction requirements of Gα i2 and Gα 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 Gα i2 -null mice, Gα 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 β-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 Gα i3 -null cells but had no effect in Gα i2 -null cells. This study demonstrates that Gα i2 , but not Gα i3 , is required for muscarinic inhibition of the β-adrenergic response in adult murine ventricular myocytes.