Originally published In Press as doi:10.1074/jbc.M414112200 on March 8, 2005
J. Biol. Chem., Vol. 280, Issue 18, 18543-18550, May 6, 2005
Insulin Stimulates Postsynaptic Density-95 Protein Translation via the Phosphoinositide 3-Kinase-Akt-Mammalian Target of Rapamycin Signaling Pathway*
Cheng-Che Lee
¶,
Chiung-Chun Huang¶,
Mei-Ying Wu, and
Kuei-Sen Hsu||
From the
Department of Pharmacology and Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan
Insulin receptors are highly enriched at neuronal synapses, but whose function remains unclear. Here we present evidence that brief incubations of rat hippocampal slices with insulin resulted in an increased protein expression of dendritic scaffolding protein postsynaptic density-95 (PSD-95) in area CA1. This insulin-induced increase in the PSD-95 protein expression was inhibited by the tyrosine kinase inhibitor, AG1024, phosphatidylinositol 3-kinase (PI3K) inhibitors, LY294002 and wortmannin, translational inhibitors, anisomycin and rapamycin, but not by LY303511 (an inactive analogue of LY294002), and transcriptional inhibitor, actinomycin D, suggesting that insulin regulates the translation of PSD-95 by activating the receptor tyrosine kinase-PI3K-mammalian target of rapamycin (mTOR) signaling pathway. A similar insulin-induced increase in the PSD-95 protein expression was detected after stimulation of the synaptic fractions isolated from the hippocampal neurons. Furthermore, insulin treatment did not affect the PSD-95 mRNA levels. In agreement, insulin rapidly induced the phosphorylation of 3-phosphoinositide-dependent protein kinase-1 (PDK1), protein kinase B (Akt), and mTOR, effects that were prevented by the AG1024 and LY294002. We also show that insulin stimulated the phosphorylation of 4E-binding protein 1 (4E-BP1) and p70S6 kinase (p70S6K) in a mTOR-dependent manner. Finally, we demonstrate the constitutive expression of PSD-95 mRNA in the synaptic fractions isolated from hippocampal neurons. Taken together, these findings suggest that activation of the PI3K-Akt-mTOR signaling pathway is essential for the insulin-induced up-regulation of local PSD-95 protein synthesis in neuronal dendrites and indicate a new molecular mechanism that may contribute to the modulation of synaptic function by insulin in hippocampal area CA1.
Received for publication, December 15, 2004
, and in revised form, February 25, 2005.
* This work was supported by Research Grant NSC93-2320-B-006-76 from the National Science Council of 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.
¶ Both authors contributed equally to this work.
|| To whom correspondence should be addressed: Dept. of Pharmacology, College of Medicine, National Cheng Kung University, No. 1, University Rd., Tainan 701, Taiwan. Tel.: 886-6-2353535 (ext. 5498); Fax: 886-6-2749296; E-mail: richard{at}mail.ncku.edu.tw.
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