HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 281, Issue 40, 30212-30222, October 6, 2006

This Article Full Text Full Text (PDF) All Versions of this Article: 281/40/30212    most recent M602156200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Viviani, B. Articles by Marinovich, M. Search for Related Content PubMed PubMed Citation Articles by Viviani, B. Articles by Marinovich, M. Social Bookmarking                      What's this?

Interleukin-1 Released by gp120 Drives Neural Death through Tyrosine Phosphorylation and Trafficking of NMDA Receptors^*

From the Laboratory of Toxicology and Center of Excellence on Neurodegenerative Diseases, Department of Pharmacological Sciences, University of Milan, 20133 Milan, Italy

Interleukin-1 is a proinflammatory cytokine implicated under pathological conditions involving NMDA receptor activation, including the AIDS dementia complex (HAD). No information is available on the molecular mechanisms recruited by native interleukin-1 produced under this type of condition. Using a sandwich co-culture of primary hippocampal neurons and glia, we investigated whether native interleukin-1 released by HIV-gp120-activated glia (i) affects NMDAR functions and (ii) the relevance on neuronal spine density and survival, two specific traits of HAD. Increased phosphorylation of NR2B Tyr-1472 was observed after 24 h of exposure of neurons to 600 pM gp120. This effect occurred only when neurons were treated in the presence of glial cells and was abolished by the interleukin-1 receptor antagonist (IL-1ra). Gp120-induced phosphorylation of NR2B resulted in a sustained elevation of intracellular Ca²⁺ in neurons and in a significant increase of NR2B binding to PSD95. Increased intracellular Ca²⁺ was prevented by 10 µM ifenprodil, that selectively inhibits receptors containing the NR2B, by interleukin-1ra and by Ca-pYEEIE, a Src family SH2 inhibitor peptide. These last two inhibitors, prevented also NR2B binding to PSD95. Finally, gp120 reduced by 35% of the total PSD95 positive spine density after 48 h of treatment and induced by 30% of the neuronal death. Again, both of these effects were blocked by Ca-pYEEIE. Altogether, our data show that gp120 releasing interleukin-1 from glia increases tyrosine phosphorylation of NMDAR. Thus, tyrosine phosphorylation may contribute to the sensitization of the receptor increasing its function and synaptic localization. Both of these effects are relevant for neurodegeneration.

Received for publication, March 7, 2006 , and in revised form, August 1, 2006.

^* This work was supported by the European Community (LSHM-CT-2004-511995, SYNSCAFF), by FISR (MDL), FISR-Neurobiotecnologie, IRCCS (MDL), FIRB (RBAU01AR5J, RBNE01BNFK), and FIRST 2004. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement"in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ These two authors contributed equally to this work.

² To whom correspondence should be addressed: Dept. of Pharmacological Sciences, Via Balzaretti 9, 20133 Milan, Italy. Tel.: 39-0-250318356; Fax: 39-0-2503183260; E-mail: Barbara.Viviani{at}unimi.it.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				S. Khanna, S. Roy, H.-A Park, and C. K. Sen Regulation of c-Src Activity in Glutamate-induced Neurodegeneration J. Biol. Chem., August 10, 2007; 282(32): 23482 - 23490. [Abstract] [Full Text] [PDF]

				T. Chernova, J. R. Steinert, C. J. Guerin, P. Nicotera, I. D. Forsythe, and A. G. Smith Neurite Degeneration Induced by Heme Deficiency Mediated via Inhibition of NMDA Receptor-Dependent Extracellular Signal-Regulated Kinase 1/2 Activation J. Neurosci., August 8, 2007; 27(32): 8475 - 8485. [Abstract] [Full Text] [PDF]