GROWTH CONE TRANSDUCTION - G0 AND GAP-43

The neuronal growth cone plays a crucial role in forming the complex brain architecture achieved during development, and similar nerve terminal mechanisms may operate to modify synaptic structure during adulthood. The growth cone leads the elongating axon towards appropriate synaptic targets by altering motility in response to a variety of extracellular signals. Independently of extrinsic clues, neurons mainfest intrinsic control of their growth and form (Banker and Cowan, 1979). Hence, there must be intracellular proteins which control nerve cell shape, so-called 'plasticity' or 'growth' genes. GAP-43 may be such a molecule (Skene and Willard, 1981; Benowitz and Lewis, 1983). For example, GAP-43 is localized to the growth cone membrane (Meiri et al. 1986; Skene et al. 1986) and can enhance filopodial formation even in non-neuronal cells (Zuber et al. 1989a). It includes a small region at the amino terminus for membrane association and perhaps growth cone targeting (Zuber et al. 1989b, Liu et al. 1991). We have found that G(o), a member of the G protein family that links receptors and second messengers, is the major non-cytoskeletal protein in the growth cone membrane (Strittmatter et al. 1990). Double staining immunohistochemistry for GAP-43 and G(o) shows that the distributions of the two proteins are quite similar. Purified GAP-43 regulates the activity of purified G(o) (Strittmatter et al. 1990), a surprising observation since GAP-43 is an intracellular protein. We have compared the mechanism of GAP-43 activation of G(o) with that of G protein-linked receptors. GAP-43 resembles receptor activation in that both serve primarily to increase the rate of dissociation of bound GDP, with consequent increase in GTP-gamma-S binding and GTPase activity. Neither affects the intrinsic rate of hydrolysis of bound GTP by G(o). They differ, however, in that pertussis toxin blocks interaction of the receptor with G(o), but not that of GAP-43. Furthermore, whereas GAP-43 activates both isolated alpha(o) subunits and alpha-beta-gamma-trimers, receptors require the presence of the beta-gamma-subunits. Thus like receptors, GAP-43 is a guanine nucleotide release protein, but of a novel class. The interactions between G(o) and GAP-43 suggest that G(o) plays a pivotal role in growth cone function, coordinating the effects of both extracellular signals and intracellular growth proteins.