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The Journal of Neuroscience, March 22, 2006, 26(12):3335-3344; doi:10.1523/JNEUROSCI.5010-05.2006

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Cellular/Molecular
An Analog of a Dipeptide-Like Structure of FK506 Increases Glial Cell Line-Derived Neurotrophic Factor Expression through cAMP Response Element-Binding Protein Activated by Heat Shock Protein 90/Akt Signaling Pathway

Xiaobo Cen,^1,2 * Atsumi Nitta,^1 * Shin Ohya,¹ Yinglan Zhao,¹ Naoya Ozawa,¹ Akihiro Mouri,¹ Daisuke Ibi,^1,7 Li Wang,² Makiko Suzuki,³ Kuniaki Saito,³ Yasutomo Ito,⁴ Tetsuya Kawagoe,⁵ Yukihiro Noda,^1,6 Yoshihisa Ito,^1,7 Shoei Furukawa,⁸ and Toshitaka Nabeshima¹

¹Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, Nagoya 466-8560, Japan, ²National Chengdu Center for Safety Evaluation of Traditional Chinese Medicine, West China Hospital, Sichuan University, Chengdu 610041, China, ³Department of Laboratory Medicine, Gifu University School of Medicine, Gifu 500-8705, Japan, ⁴Equipment Center for Research and Education, Nagoya University Graduate School of Medicine, Nagoya 466-8560, Japan, ⁵Department of Research and Development, Initium, Tokyo, 107-0062, Japan, ⁶Division of Clinical Science in Clinical Pharmacy Practice, Management and Research, Faculty of Pharmacy, Meijo University, Nagoya 468-8503, Japan, ⁷Department of Pharmacology, College of Pharmacy, Nihon University, Funabashi-shi, Chiba 274-8555, Japan, and ⁸Laboratory of Molecular Biology, Gifu Pharmaceutical University, Gifu 502-8585, Japan

Correspondence should be addressed to Toshitaka Nabeshima, Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, Tsuruma-Cho, Showa-ku, Nagoya 466-8560, Japan. Email: tnabeshi{at}med.nagoya-u.ac.jp

Glial cell line-derived neurotrophic factor (GDNF) is an important neurotrophic factor that has therapeutic implications for neurodegenerative disorders. We previously showed that leucine-isoleucine (Leu-Ile), an analog of a dipeptide-like structure of FK506 (tacrolimus), induces GDNF expression both in vivo and in vitro. In this investigation, we sought to clarify the cellular mechanisms underlying the GDNF-inducing effect of this dipeptide. Leu-Ile transport was investigated using fluorescein isothiocyanate-Leu-Ile in cultured neurons, and the results showed the transmembrane mobility of this dipeptide. By liquid chromatography-mass spectrometry and quartz crystal microbalance assay, we identified heat shock cognate protein 70 as a protein binding specifically to Leu-Ile, and molecular modeling showed that the ATPase domain is the predicted binding site. Leu-Ile stimulated Akt phosphorylation, which was attenuated significantly by heat shock protein 90 (Hsp90) inhibitor geldanamycin (GA). Moreover, enhanced interaction between phosphorylated Akt and Hsp90 was detected by immunoprecipitation. Leu-Ile elicited an increase in cAMP response element binding protein (CREB) phosphorylation, which was inhibited by GA, indicating that CREB is a downstream target of Hsp90/Akt signaling. Leu-Ile elevated the levels of GDNF mRNA and protein expression, whereas inhibition of CREB blocked such effects. Leu-Ile promoted the binding activity of phosphorylated CREB with cAMP response element. These findings show that CREB plays a key role in transcriptional regulation of GDNF expression induced by Leu-Ile. In conclusion, Leu-Ile activates Hsp90/Akt/CREB signaling, which contributes to the upregulation of GDNF expression. It may represent a novel lead compound for the treatment of dopaminergic neurons or motoneuron diseases.

Key words: GDNF; dipeptide; FK506; Hsp90; Hsc70; CREB

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Received Aug. 6, 2005; revised Feb. 2, 2006; accepted Feb. 2, 2006.

Correspondence should be addressed to Toshitaka Nabeshima, Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, Tsuruma-Cho, Showa-ku, Nagoya 466-8560, Japan. Email: tnabeshi{at}med.nagoya-u.ac.jp

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