GAP-43 as a modulator of G protein transduction in the growth cone

Much circumstantial evidence that GAP-43 is involved in neuronal growth cone function has accumulated over the last ten years. The expression of the protein is closely correlated both temporally and spatially with periods of axonal outgrowth, and the protein is highly concentrated in the growth cone membrane. There is direct evidence that overexpression of the protein can alter cell shape. This review focuses on the molecular mechanisms whereby GAP-43 could exert these actions. One important requirement for GAP-43 function is its localization to appropriate regions of the cell. The ability of this hydrophilic protein to associate with membrane fractions is determined by a short 10 amino acid stretch of the amino terminus of the protein, which contains two cysteine residues subject to palmitoylation. Whether this region can direct growth cone targeting in neurons is not yet clear. Once appropriately localized, GAP-43 may modulate complex cellular properties such as growth cone motility, synaptic plasticity and neurotransmitter release. One possible molecular mechanism for these cellular changes in GAP-43 regulation of the GTP-binding protein, G(o). The observation that the growth cone membrane contains extremely high concentrations of G(o) led us to investigate the interaction of G(o) and GAP-43. There is evidence that G protein-mediated transduction systems can control the same cellular functions thought to be altered by GAP-43: growth cone motility, neurotransmitter release and synaptic plasticity. Purified GAP-43 does stimulate guanine nucleotide binding to G(o). Its action in stimulating GDP release is quite similar to that of G protein-coupled transmembrane receptors.(ABSTRACT TRUNCATED AT 250 WORDS)