A Review and Predictive Models of Gang ioside Uptake by Biological Membranes

Gangliosides are sialic acid-containing glycolipids that are present in the plasma membrane of all mammalian cells (Ledeen and Yu, 1982; Stults et al., 1989). They are particularly abundant in neurons, comprising 10% of the total lipids (Wiegandt, 1971; Ledeen, 1978). Gangliosides are located asymmetrically in the plasmalemma with their hydrophilic, oligosaccharide chains protruding from the extracellular surface and their nonpolar portion (ceramide) inserted into the hydrophobic regions of the membrane (Wiegandt, 197 1, 1982; Bretscher, 1973; Fishman and Brady, 1976; Hansson et al., 1977). Gangliosides added exogenously to culture media are taken up by a wide range of cells in vitro (Leon et al., 1982, 1988; Ghidoni et al., 1989; Riboni et al., 1990), including astrocytes (Masco et al., 1989), glioma (Fishman et al., 1980), and neuroblastoma (Leskawa et al., 1989) cells, fibroblasts (Keenan et al., 1974; Fishman et al., 1977; Giglioni et al., 1990), both red and white human blood cells (Ackerman et al., 1980), and leukemic and nonleukemic lymphocytes (Krishnaraj et al., 1980). Gangliosides delivered to cells this way have a variety of biological effects depending upon the cell type. One such effect that has been studied extensively is neurite formation (neuritogenesis) by neuronal cells (Morgan and Seifert, 1979; Byrne et al., 1983; Ferrari et al., 1983; Facci et al., 1984; Schengrund, 1990). Exogenous gangliosides are incorporated into the plasma membrane (Cuatrecasas, 1973; Keenan et al., 1974, 1975; Gill and King, 1975; Holmgren et al., 1975; Naiki and Marcus, 1976; Sharom and Grant, 1978; Yamakawa and Nagai, 1978; Kanda et al., 1982~ ; Facci et al., 1984; Riboni and Tettamanti, 199 1) by a timeand concentration-dependent process (Moss et al., 1976; Morgan and Seifert, 1979; Skaper et al., 1988) without a change in their chemical nature, so that, following incorporation, they are functionally and metabolically active (Moss et al., 1976). The mechanisms through which gangliosides exert their effects are not clear, but several have been proposed (Fass and Ramirez, 1984; Karpiak and Mahadik, 1984; Leon et al., 1984; Schonfeld et al., 1984; Toffano et al., 1984; Vaswani et al., 1990; Chu and Sharom, 199 1). These include alterations of several enzyme activities (Partington and Daly, 1979; Leon et al., 1981; Yates et al., 1988; Chan, 1989), protein phosphorylation (Bremer et al., 1984; Chan, 1988; Tsuji et al., 1988; Kai-Foon, 1989; Rafi et al., 1990; Bassi et al., 199 1 ; Weis and Davis, 199 l), some second messenger systems (Leon et al., 1982), and membrane permeability (Sarti et al., 1990). Although the addition of exogenous gangliosides is a widely used approach to studying their effects on cellular systems in vitro, the conditions under which they are added have not yet been standardized, making specific comparisons among different experiments difficult. In this article, we review many of the variables that are involved in the uptake and metabolism of exogenous gangliosides by cells and biological membranes. Under Predictive Models of Ganglioside Uptake, we present equations we have developed that relate the amounts of incorporated ganglioside to the major variables affecting ganglioside uptake. Under Factors that Affect Net Ganglioside Incorporation, we discuss several of the variables that are either qualitative or quantitative, but for which currently available data are insufficient to treat in a quantitative fashion.