Ganglioside/calmodulin kinase II signal inducing cdc42-mediated neuronal actin reorganization

Cell surface glycoconjugates are thought to mediate cell-cell recognition and play roles in neuronal development and functions. We demonstrated here that exposure of neuronal cells to nanomolar levels of gangliosides Neu5Acalpha-8Neu5Acalpha3Galbeta4GlcCer, Galbeta3GalNAcbeta4(Neu5Acalpha8Neu5Acalpha3)Galbeta4GlcCer (GD1b), Neu5Acalpha3Galbeta3GaINAcbeta4(Neu-5Acalpha8Neu5Acalpha3)Galbeta4GlcCer (GT1b) or its oligosaccharide portion induced a rapid and transient activation of Ca2+/ calmodulin-dependent protein kinase II (CaM-KII) in the sub-plasmalemma. Galbeta3GaINAcbeta4(Neu5Acalpha3)Galbeta4GLcCer (LGM1), GaINAcbeta4(Neu5Acalpha3)Galbeta4GlcCer, Neu5Acalpha3Galbeta4GlcCer, Neu5Acalpha3GaIbeta3GaINAcbeta4Neu5Acalpha3)GaIbeta4GIcCer (GD1a), and Neu5Acalpha8Neu5Acalpha3Galbeta3GaINAcbeta4(Neu5Acalpha8Neu5Acalpha3)-GaIbeta4GIcCer were ineffective. GT1b and GD1b stimulated transient elevation of bulk cytosolic Ca2+ levels while GM1 slightly elevated the levels and GD1a did not. Thus, the cytosolic Ca2+ elevation by the gangliosides may trigger the CaM-KII activation. The treatment was accompanied by peripheral actin polymerization and filopodia formation in NG108-15 cells and primary hippocampal neurons, but not in glial cells. CaM-KII inhibitors blocked both CaM-KII activation and the subsequent filopodia formation. A small G-protein cdc42 was a potential downstream target of CaM-KII activated by the gangliosides. These results suggest that oligosaccharicles of the gangliosides serve as potential regulators of the filopodia formation in neuronal cells by triggering the activation of CaM-KII followed by cdc42 up-regulation via a cell surface receptor-like component. The filopodia formation induced by the gangliosides may have a physiological relevance because long-term exposure of hippocampal neurons to GT1b oligosaccharide induced advanced dendritogenesis. Furthermore, exposure of cerebellar neurons to GT1b oligosaccharide facilitated CaM-KII-dependent dendritic outgrowth and branch formation of cerebellar Purkinje neurons, in which actin isoforms were localized to motile structures in dendrites. Thus, the ganglioside/CaM-KII signal plays a role in modulating dendritic morphogenesis by inducing cdc42-mediated actin reorganization. (C) 2003 IBRO. Published by Elsevier Science Ltd. All rights reserved.