Antibodies to glycolipids have been implicated in the pathogenesis of several immune-mediated PNS demyelinating diseases. This study focuses on antibodies to galactocerebroside (GalC) and sulfatide and on the B subunit of cholera toxin (CTB), which reacts with GM1 ganglioside, to examine whether these agents have any direct effects on Schwann cells (SC) as measured by Ca++ responses. While surface levels of GalC and sulfatide were markedly upregulated by 8 Br-cAMP treatment, as reported by others, very little expression of surface GM1 ganglioside was detected with or without 8 Br-cAMP treatment. Schwann cells, under either condition, showed no changes in intracellular Ca++ levels when exposed to purified monoclonal antibodies reacting with GalC or sulfatide. Thus upregulation of surface levels of GalC or sulfatide does not lead to antibody-induced Ca++ influx, in contrast to previous findings in mature oligodendrocytes (OLs) exposed to antibodies to GalC. Further, cross-linking with one of the antibodies (R-mAb) did not produce Ca++ responses. No Ca++ responses were elicited by CTB in Schwann cells either with or without 8 Br-cAMP treatment. Since surface binding of CTB was very low and sparsely punctate in Schwann cells +/- 8 Br-cAMP, we tested whether increasing levels of GM1 ganglioside on the surface would lead to induction of a Ca++ signaling pathway, as reported for fibroblasts. GM1 ganglioside on the surface of SC was markedly increased by exposing cells to exogenous GM1 ganglioside, but no Ca++ responses were observed in the treated cells. Thus undifferentiated or partially differentiated SC lack the glycoconjugate-mediated Ca++ signaling pathways found in mature OLs or fibroblasts.