Binding of rapamycin analogs to calcium channels and FKBP52 contributes to their neuroprotective activities
| Autor: | Andrew R. Wood, Guy T. Carter, Edmund I. Graziani, Menelas N. Pangalos, Kevin Pong, Frank E. Koehn, Benfang Ruan, Ronald L. Magolda, Magid Abou-Gharbia, Robert A. Crozier, Flora Jow, Frann Bennett, Danni Liu, Mark R. Bowlby, Peter H. Reinhart, Xidong Feng, Mary Lynn T. Mercado, Leonard A. McDonald, Shi Liang, Yi Chen, Jerauld S. Skotnicki, Margaret M. Zaleska, David von Schack |
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| Rok vydání: | 2008 |
| Předmět: |
Patch-Clamp Techniques
Neurite Pharmacology Ligands Tacrolimus Binding Proteins Neuroblastoma Neurites Animals Humans Patch clamp Immunophilins Binding selectivity Neurons Sirolimus Multidisciplinary biology Voltage-dependent calcium channel FKBP52 Rats Electrophysiology Stroke FKBP Models Chemical Physical Sciences biology.protein Calcium Calcium Channels Immunosuppressive Agents Protein Binding Neurotrophin |
| Zdroj: | Proceedings of the National Academy of Sciences. 105:33-38 |
| ISSN: | 1091-6490 0027-8424 |
| Popis: | Rapamycin is an immunosuppressive immunophilin ligand reported as having neurotrophic activity. We show that modification of rapamycin at the mammalian target of rapamycin (mTOR) binding region yields immunophilin ligands, WYE-592 and ILS-920, with potent neurotrophic activities in cortical neuronal cultures, efficacy in a rodent model for ischemic stroke, and significantly reduced immunosuppressive activity. Surprisingly, both compounds showed higher binding selectivity for FKBP52 versus FKBP12, in contrast to previously reported immunophilin ligands. Affinity purification revealed two key binding proteins, the immunophilin FKBP52 and the β1-subunit of L-type voltage-dependent Ca 2+ channels (CACNB1). Electrophysiological analysis indicated that both compounds can inhibit L-type Ca 2+ channels in rat hippocampal neurons and F-11 dorsal root ganglia (DRG)/neuroblastoma cells. We propose that these immunophilin ligands can protect neurons from Ca 2+ -induced cell death by modulating Ca 2+ channels and promote neurite outgrowth via FKBP52 binding. |
| Databáze: | OpenAIRE |
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