G alpha(i2) but not G alpha(i3) is required for muscarinic inhibition of contractility and calcium currents in adult cardiomyocytes

Parasympathetic stimulation of the heart acts through M-2-muscarinic acetyl choline receptors to regulate ion channel activity and subsequent inotropic status. Although muscarinic signal transduction is mediated via pertussis toxin-sensitive G proteins G alpha (i/o), the specific signal transduction requirements of G alpha (i2) and G alpha (i3) in mediating muscarinic regul ated L-type calcium currents (I-Ca/L), intracellular calcium, and cell cont ractility remain to be determined. Adult ventricular myocytes were isolated from G alpha (i2)-null mice, G alpha (i3)-null mice, and their wild-type l ittermates. Cell shortening, intracellular calcium levels, and I-Ca,I-L wer e all measured in response to isoproterenol, a beta -adrenergic receptor ag onist, and carbachol, a cholinergic receptor agonist. With isoproterenol st imulation, myocytes from all groups demonstrated a marked increase in calci um currents, correlating with augmented intracellular calcium transient amp litude and cell shortening. Carbachol significantly attenuated the isoprote renol response in wild-type and G alpha (i3)-null cells but had no effect i n G alpha (i2)-null cells. This study demonstrates that G alpha (i2), but n ot G alpha (i3), is required for muscarinic inhibition of the beta -adrener gic response in adult murine ventricular myocytes.