Abstract:
: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 beta1-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.
journal_name
Proc Natl Acad Sci U S Aauthors
Ruan B,Pong K,Jow F,Bowlby M,Crozier RA,Liu D,Liang S,Chen Y,Mercado ML,Feng X,Bennett F,von Schack D,McDonald L,Zaleska MM,Wood A,Reinhart PH,Magolda RL,Skotnicki J,Pangalos MN,Koehn FE,Carter GT,Abou-Gharbia Mdoi
10.1073/pnas.0710424105subject
Has Abstractpub_date
2008-01-08 00:00:00pages
33-8issue
1eissn
0027-8424issn
1091-6490pii
0710424105journal_volume
105pub_type
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