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Activation of phospholipase C pathways by a synthetic chondroitin sulfate-E tetrasaccharide promotes neurite outgrowth of dopaminergic neurons

Sotogaku, Naoki and Tully, Sarah E. and Gama, Cristal I. and Higashi, Hideho and Tanaka, Masatoshi and Hsieh-Wilson, Linda C. and Nishi, Akinori (2007) Activation of phospholipase C pathways by a synthetic chondroitin sulfate-E tetrasaccharide promotes neurite outgrowth of dopaminergic neurons. Journal of Neurochemistry, 103 (2). pp. 749-760. ISSN 00223042. doi:10.1111/j.1471-4159.2007.04849.x. https://resolver.caltech.edu/CaltechAUTHORS:20150521-205010629

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Abstract

In dopaminergic neurons, chondroitin sulfate (CS) proteoglycans play important roles in neuronal development and regeneration. However, due to the complexity and heterogeneity of CS, the precise structure of CS with biological activity and the molecular mechanisms underlying its influence on dopaminergic neurons are poorly understood. In this study, we investigated the ability of synthetic CS oligosaccharides and natural polysaccharides to promote the neurite outgrowth of mesencephalic dopaminergic neurons and the signaling pathways activated by CS. CS-E polysaccharide, but not CSA, -C or -D polysaccharide, facilitated the neurite outgrowth of dopaminergic neurons at CS concentrations within the physiological range. The stimulatory effect of CS-E polysaccharide on neurite outgrowth was completely abolished by its digestion into disaccharide units with chondroitinase ABC. Similarly to CS-E polysaccharide, a synthetic tetrasaccharide displaying only the CS-E sulfation motif stimulated the neurite outgrowth of dopaminergic neurons, whereas a CS-E disaccharide or unsulfated tetrasaccharide had no effect. Analysis of the molecular mechanisms revealed that the action of the CS-E tetrasaccharide was mediated through midkine-pleiotrophin/protein tyrosine phosphatase ζ and brain-derived neurotrophic factor/tyrosine kinase B receptor pathways, followed by activation of the two intracellular phospholipase C (PLC) signaling cascades: PLC/protein kinase C and PLC/inositol 1,4,5-triphosphate/inositol 1,4,5-triphosphate receptor signaling leading to intracellular Ca^(2+) concentration-dependent activation of Ca^(2+)/calmodulin-dependent kinase II and calcineurin. These results indicate that a specific sulfation motif, in particular the CS-E tetrasaccharide unit, represents a key structural determinant for activation of midkine, pleiotrophin and brain-derived neurotrophic factor-mediated signaling, and is required for the neuritogenic activity of CS in dopaminergic neurons.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1111/j.1471-4159.2007.04849.xDOIArticle
http://onlinelibrary.wiley.com/doi/10.1111/j.1471-4159.2007.04849.x/abstractPublisherArticle
ORCID:
AuthorORCID
Hsieh-Wilson, Linda C.0000-0001-5661-1714
Additional Information:© 2007 The Authors. Journal Compilation © 2007 International Society for Neurochemistry Received December 12, 2006; revised manuscript received June 2, 2007; accepted June 6, 2007. We thank Drs Hideki Hida and Hitoo Nishino for teaching the preparation of primary mesencephalic neuronal culture. This work was supported by the Human Frontiers Science Program (RGY0072/2002-C, LCH-W and AN), the American Cancer Society (RSG-05-106-01-CDD, LCH-W), the Tobacco-Related Disease Research Program (14RT-0034, LCH-W), the Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (NS and AN), and the Kaibara Morikazu Medical Science Promotion Foundation (NS).
Funders:
Funding AgencyGrant Number
Human Frontiers Science ProgramRGY0072/2002-C
American Cancer SocietyRSG-05-106-01-CDD
California Tobacco-Related Disease Research Program14RT-0034
Japan Society for the Promotion of Science (JSPS)UNSPECIFIED
Kaibara Morikazu Medical Science Promotion FoundationUNSPECIFIED
Issue or Number:2
DOI:10.1111/j.1471-4159.2007.04849.x
Record Number:CaltechAUTHORS:20150521-205010629
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20150521-205010629
Official Citation:Sotogaku, N., Tully, S. E., Gama, C. I., Higashi, H., Tanaka, M., Hsieh-Wilson, L. C. and Nishi, A. (2007), Activation of phospholipase C pathways by a synthetic chondroitin sulfate-E tetrasaccharide promotes neurite outgrowth of dopaminergic neurons. Journal of Neurochemistry, 103: 749–760. doi: 10.1111/j.1471-4159.2007.04849.x
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:57757
Collection:CaltechAUTHORS
Deposited By: Donna Wrublewski
Deposited On:22 May 2015 04:25
Last Modified:10 Nov 2021 21:54

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