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J. Biol. Chem., Vol. 280, Issue 32, 29322-29333, August 12, 2005

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N-Methyl-D-aspartate Receptor Subtype Mediated Bidirectional Control of p38 Mitogen-activated Protein Kinase^*

Elisa A. Waxman and David R. Lynch¶||**

From the Departments of Pharmacology, Neurology, and ^¶Pediatrics, University of Pennsylvania School of Medicine and the ^||Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104

N-methyl-D-aspartate receptor (NMDAR) stimulation activates many downstream mechanisms involved in both cell survival and cell death. The manner in which the NMDAR regulates one of these pathways, the p38 mitogen-activated protein kinase (p38) pathway, is currently unknown. In the present study, we have defined a developmental-, concentration-, and time-dependent phosphorylation and subsequent dephosphorylation of p38. In cultured hippocampal neurons 7-8 days in vitro (DIV7-8), NMDAR stimulation leads to a concentration-dependent increase in p38 phosphorylation (phospho-p38). However, in more mature neurons (>DIV17) application of NMDA produces concentration-dependent effects, such that low concentrations result in sustained increases in phospho-p38 levels, and high concentrations dephosphorylate p38 within 5 min. Conantokin G, an antagonist of NR1/2A/2B and NR1/2B receptors, inhibits p38 phosphorylation, while NR1/2B-specific antagonists prevent the rapid dephosphorylation of p38 without affecting p38 activation. Furthermore, inhibition of calcineurin prevents the activation of p38, whereas inhibition of phosphoinositide 3-kinase (PI3K) prevents the rapid dephosphorylation of p38. Our results support the presence of subtype-dependent pathways regulating p38 activation and deactivation: one involves NR1/2A/2B receptors activating calcineurin and resulting in p38 phosphorylation, and the other utilizes NR1/2B receptors binding to and activating PI3K and leading to the dephosphorylation of p38 in a manner involving both NR1/2A/2B receptor activation and tyrosine phosphorylation of NR2B. The ability of NMDAR subtype-specific mechanisms to regulate p38 has implications for NMDAR-mediated synaptic plasticity, gene regulation, and excitotoxicity.

Received for publication, February 23, 2005 , and in revised form, June 1, 2005.

^* This work was supported by National Institutes of Health Grants NS45986 (to D. R. L.), and T32 MH 14654 (to E. A. W.). 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.

^** To whom correspondence should be addressed: 502 Abramson Bldg., Children's Hospital of Philadelphia, 3615 Civic Center Blvd., Philadelphia, PA 19104. Tel.: 215-590-2242; Fax: 215-590-3779: E-mail: lynch{at}pharm.med.upenn.edu.

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