Galpha(i2), but not Galpha(i3), is specifically required for muscarinic inhibition of beta-adrenergic-stimulated contractility and calcium currents in adult cardiomyocytes.
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 Galpha(i/o), the specific signal transduction requirements of Galpha(i2) and Galpha(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 Galpha(i2)-null mice, Galpha(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 beta-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 Galpha(i3)-null cells but had no effect in Galpha(i2)-null cells. This study demonstrates that Galpha(i2), but not Galpha(i3), is required for muscarinic inhibition of the beta-adrenergic response in adult murine ventricular myocytes.
Nagata et al. (Fri,) studied this question.