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J. Biol. Chem., Vol. 279, Issue 13, 12286-12292, March 26, 2004

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Rap1-induced p38 Mitogen-activated Protein Kinase Activation Facilitates AMPA Receptor Trafficking via the GDI·Rab5 Complex

POTENTIAL ROLE IN (S)-3,5-DIHYDROXYPHENYLGLYCINE-INDUCED LONG TERM DEPRESSION^*

Chiung-Chun Huang, Jia-Lin You, Mei-Ying Wu, and Kuei-Sen Hsu

From the Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan City 701, Taiwan

Recent evidence has emphasized the importance of p38 mitogen-activated protein kinase (MAPK) in the induction of metabotropic glutamate receptor (mGluR)-dependent long term depression (LTD) at hippocampal CA3-CA1 synapses. However, the cascade responsible of mGluR to activate p38 MAPK and the signaling pathway immediately downstream from it to induce synaptic depression is poorly understood. Here, we show that transient activation of group I mGluR with the selective agonist (S)-3,5-dihydroxyphenylglycine (DHPG) activates p38 MAPK through G protein -subunit, small GTPase Rap1, and MAPK kinase 3/6 (MKK3/6), thus resulting in mGluR5-dependent LTD. Furthermore, our data clearly show that an accelerating AMPA receptor endocytosis by stimulating the formation of guanyl nucleotide dissociation inhibitor-Rab5 complex is a potential downstream processing of p38 MAPK activation to mediate DHPG-LTD. These results suggest an important role for Rap1-MKK3/6-p38 MAPK pathway in the induction of mGluR-dependent LTD by directly coupling to receptor trafficking machineries to facilitate the loss of synaptic AMPA receptors.

Received for publication, November 25, 2003 , and in revised form, January 5, 2004.

^* This work was supported by research grants from the Academic Excellence Program of the Ministry of Education (89-B-FA08-1-4) and National Health Research Institute (NHRI-EX92-9215NI) (Taipei, Taiwan). 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: Dept. of Pharmacology, College of Medicine, National Cheng Kung University, No. 1, University Rd., Tainan City 701, Taiwan. Tel.: 886-6-2353535 (ext. 5498); Fax: 886-6-2749296; E-mail: richard{at}mail.ncku.edu.tw.

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