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

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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 Gαi/o, the specific signal transduction requirements of Gαi2 and Gαi3 in mediating muscarinic regulated L-type calcium currents (ICa, L), intracellular calcium, and cell contractility remain to be determined. Adult ventricular myocytes were isolated from Gαi2-null mice, Gαi3-null mice, and their wild-type littermates. Cell shortening, intracellular calcium levels, and ICa, 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 Gαi3-null cells but had no effect in Gαi2-null cells. This study demonstrates that Gαi2, but not Gαi3, is required for muscarinic inhibition of the β-adrenergic response in adult murine ventricular myocytes.