G0, a GTP-binding protein that transduces information from transmembrane receptors, has been found to be a major component of the neuronal growth cone membrane. GAP-43, an intracellular growth cone protein closely associated with neuronal growth, stimulates GTP-gamma-S binding to G0. It does so through an amino-terminal domain homologous to G-linked transmembrane receptors. Thus, G0 in the growth cone may be regulated by intracellular as well as extracellular signals.

Heterotrimeric G proteins, composed of G␣ and G␤␥ subunits, transmit signals from cell surface receptors to cellular effector enzymes and ion channels. The G␣ o protein is the most abundant G␣ 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 Ca 2؉ 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␣ o , we have generated mice lacking both isoforms of G␣ o by homologous recombination. Surprisingly, the nervous system is grossly intact, despite the fact that G␣ o makes up 0.2-0.5% of brain particulate protein and 10% of the growth cone membrane. The G␣ o ؊͞؊ mice do suffer tremors and occasional seizures, but there is no obvious histologic abnormality in the nervous system. In contrast, G␣ 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␣ subunits (G␣ s , G␣ q , and G␣ i ) are unchanged in the hearts of G␣ o ؊͞؊ mice, but the amount of G␤␥ is decreased. Whichever subunit, G␣ o or G␤␥, carries the signal forward, these studies show that muscarinic inhibition of L-type Ca 2؉ channels requires coupling of the muscarinic receptor to G␣ o . Other cardiac G␣ subunits cannot substitute.Heterotrimeric G proteins, composed of G␣ and G␤␥ subunits, transmit signals from cell surface receptors to cellular effector enzymes and ion channels. One type of G␣ subunit, G␣ o , is extremely abundant in the brain, where it was first identified (1, 2), but it is also expressed in heart, pituitary, and pancreas. In addition to G␣ o , both the brain and the heart contain other closely related G␣ subunits (for example, members of the G␣ i group that are, like G␣ o , substrates for ADP ribosylation by pertussis toxin), as well as G␣ s (which stimulates adenylyl cyclase) and G␣ q (which stimulates phospholipase C␤).The exact function of G␣ o in heart and brain is not known. It is an extremely abundant protein in the nervous system, making up 0.2-0.5% of brain particulate protein (3, 4) and 10% of the growth cone membrane (5). In the nervous system, G␣ o has been postulated to play several roles. The ability of G␣ o to bind GTP␥S can be modulated by GAP43 (neuromodulin), an abundant growth cone protein that is important for neuronal pathfinding (5). Potentially, G␣ o could be part of the signaling cascade that regulates neuronal guidance. Its appearance in the mouse central nervous system is consistent with such a role, since it begins to appear as neurons terminally differentiate and increases as they send out processes (6). The G␣ o protein is conserved in Drosophila, w...