G alpha(0) is necessary for muscarinic regulation of Ca2+ channels in mouse heart

Heterotrimeric G proteins, composed of Ga and G beta gamma subunits, transmit signals from cell surface receptors to cellular effector enzymes and ion channels. The Ga, protein is the most abundant Ga subtype in the nervous system, but it is also found in the heart, Its function is not completely known, although it is required for regulation of N-type Ca2+ channels in GH(3) cells and also interacts with GAP43, a major protein in growth cones, suggesting a role in neuronal pathfinding, To analyze the function of G alpha(o), we have generated mice lacking both isoforms of G alpha(o) by homologous recombination, Surprisingly, the nervous system is grossly intact, despite the fact that G alpha(o) makes up 0.2-0.5% of brain particulate protein and 10% of the growth cone membrane, The G alpha(o)-/- mice do suffer tremors and occasional seizures, but there is no obvious histologic abnormality in the nervous system, In contrast, G alpha(o)-/- mice have a clear and specific defect in ion channel regulation in the heart, Normal muscarinic regulation of L-type calcium channels in ventricular myocytes is absent in the mutant mice, The L-type calcium channel responds normally to isoproterenol, but there is no evident muscarinic inhibition, Muscarinic regulation of atrial K+ channels is normal, as is the electrocardiogram. The levels of other G alpha subunits (G alpha(s), G alpha(q), and G alpha(i)) are unchanged in the hearts of G alpha(o)-/- mice, but the amount of G beta gamma is decreased. Whichever subunit, G alpha(o) or G beta gamma, carries the signal forward, these studies show that muscarinic inhibition of L-type Ca2+ channels requires coupling of the muscarinic receptor to G alpha(o). Other cardiac G alpha subunits cannot substitute.