Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 1998 Oct 2;273(40):26001-7.
doi: 10.1074/jbc.273.40.26001.

Glucosylceramide synthase inhibitor inhibits the action of nerve growth factor in PC12 cells

T Mutoh  1 , A Tokuda, J Inokuchi, M Kuriyama
Affiliations
Free article

Glucosylceramide synthase inhibitor inhibits the action of nerve growth factor in PC12 cells

T Mutoh et al. J Biol Chem. .
Free article

Abstract

Previous studies have shown that the ceramide analogue, D-threo-1-phenyl-2-decanoylamin-3-morpholino-propanol (D-PDMP), inhibits glucosylceramide synthase and thus leads to extensive depletion of glycosphingolipids derived from glucosyl ceramide. Our previous studies have shown that cholera toxin B subunit, which specifically binds to the cell surface ganglioside GM1, and GM1 itself can enhance the action of nerve growth factor (NGF) in responsive cells by enhancing the NGF-induced autophosphorylation of the high affinity NGF receptor, Trk. Using D-PDMP, we examined the effects of the inhibition of the biosynthesis of glycosphingolipids on intracellular NGF signaling pathway. D-PDMP was found to inhibit NGF-induced neurite outgrowth of PC12 cells. Moreover, D-PDMP clearly inhibited NGF-induced autophosphorylation of Trk and prevented the activation of phosphatidylinositol 3-kinase and mitogen-activated protein kinase, downstream targets of Trk-initiated intracellular protein kinase cascades. These effects of D-PDMP were abolished by the addition of GM1 but not by the addition of other ganglioside subspecies to the culture medium. Furthermore, the effect of D-PDMP seemed to be specific for the Trk receptor, because intracellular signaling pathway of epidermal growth factor was not affected by D-PDMP. Dimethylsphingosine and the cell-permeable analogue, C2-ceramide, did not show such a strong inhibitory effect on neurite outgrowth or on the autophosphorylation of Trk. The present results and our previous observations clearly demonstrate that Trk requires endogenous gangliosides, especially GM1, for its normal function in mediating the neurotrophic activity of NGF at least in PC12 cells.

PubMed Disclaimer

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

Publication types

MeSH terms

LinkOut - more resources