The main objective of this project is to establish a unified hypothesis for the biological action of gangliosides as biomodulators. Gangliosides are glycosphingolipids present in the membranes of a number of different cell types, and are especially abundant in neurons and myelin. These molecules have been implicated to play important roles in communication such as neurotransmission, neurite outgrowth and synaptogenesis, neuronal regeneration, differentiation, and development. Our studies revealed that gangliosides may act as biomodulators which could mediate their effects through phosphorylation and dephosphorylation of target protein substrates. Gangliosides can modulate the enzymic activities of at least three different protein kinases, namely, the novel ganglioside-stimulated and ganglioside-inhibited protein kinases, and the ubiquitous protein kinase C. These glycosphingolipids also can modulate the states of phosphorylation of certain proteins by exerting substrate-directed effects. Thus, it seems likely that perturbation of gangliosides can confer a synchronistic action on the regulation of these ganglioside- modulated protein phosphorylation systems. As a consequence, various physiological responses can be attained synergistically. Other related on-going studies are: (1) elucidation of the molecular mechanisms through which gangliosides and protein phosphorylation may affect viral proliferation; (2) investigation on the nature of molecular interactions involved in the formation and maintenance of myelin's multilamellar structures; (3) determination of the modes of action of neurotoxins especially those which can interact with gangliosides; (4) identification of the nature and function of HIV-receptor(s) in brain and subsequent investigation of the roles of gangliosides and protein phosphorylation involved in the regulation of infectivity and of other receptor functions.
