Ganglioside receptors: a brief overview and introductory remarks.

Gangliosides are typical amphipathic molecules organized in plasma membranes with their hydrophobic ceramide moiety inserted into the lipid bilayer and their hydrophilic, ionogenic group faced towards the outer environment of cells.1This model of ganglioside organization in membranes, as well as the occurrence of a “specific” interaction of gangliosides with various bioactive factors, favors the idea that gangliosides are acting as receptors for toxins, hormones, and other bioactive factors. The idea has been endorsed by the specific interaction of cholera toxin subunit with GM1 and by the ability of GM1 to inactivate the toxin’s biological activities and to furnish cells the toxin-dependent adenylate cyclase response when GM1 is exogenously added to the insusceptible cells. Bioactive factors which show interaction with various kinds of glycolipids are listed in Table 1, and general implications of such interaction involving ganglioside receptors have been reviewed repeatedly;2–5 however, if one is allowed to include any protein, regardless of the absence of clear biologic activity, the list of proteins that interact with gangliosides would be much longer. The fact that gangliosides interact with bioactive factors may justify an interpretation of receptor activity in some cases; nevertheless, the interaction per se does not necessarily lead us to assume that gangliosides are the receptors in general. The major conflict in accepting the idea of ganglioside receptors can be summarized in four items as described below: 1) Gangliosides interact with a large variety of proteins including serum albumin,6 amphipathic membrane proteins,7 etc.; therefore, interactions such as those listed in Table 1 may merely represent a few of many widely occurring ionic interactions whose biological significance is yet undetermined. The interaction of GM1 with cholera toxin is, of course, highly specific. 2) The common gangliosides (particularly GT1 and GD1b) inhibit the binding of various glycoprotein hormones (thyrotropin, chorionic gonadotropin and luteinizing hormone) to target tissue membranes.16–18 Various gangliosides (GM2 and GT) inhibit both mouse and human interferon activity.21–23Similarly, the same gangliosides interact with different bacterial toxins (see Table 1). These non-specific interactions of gangliosides with hormones, interferon, and toxins conflict with the fact that toxic or hormonal activities of these factors are highly specific to target cells. Furthermore, the interferon activity is highly species-specific, human interferon acting on human cells but not on mouse cells and vice versa. 3) Some natural target cells for a specified bioactive factor are lacking in the expected ganglioside which showed the strongest interaction with the specified bioactive factor. Human intestinal epithelia, which is the primary target of cholera toxin, had an extremely low content of GM1, while the intestinal epithelia of some other animals which are not susceptible to cholera infection had a large quantity of GM1. Normal rat thyroid cell lines with high-affinity functional receptors for thyrotropin had none of the higher gangliosides postulated as the thyrotropin receptor.31 Some fibroblasts, such as BHK and NIL, which have a high content of fibronectin at the cell surface had no GT or GD1b ganglioside, while other fibroblasts, such as 3T3 cells, which have a low quantity of fibronectin have a high quantity of higher gangliosides. 4) In several cases high affinity receptors for those biological factors have been isolated from target cells and characterized as protein, and the binding to gangliosides is generally of much lower specificity and affinity (with the exception of GM1 for cholera toxin.