title: Binding of rapamycin analogs to calcium channels and FKBP52 contributes to their neuroprotective activities.
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.
authors.affiliation: Chemical and Screening Sciences, Wyeth Research, 401 North Middletown Road, Pearl River, NY 10965, USA.
authors.forename: Benfang
authors.initials: B
authors.lastname: Ruan
authors.forename: Kevin
authors.initials: K
authors.lastname: Pong
authors.forename: Flora
authors.initials: F
authors.lastname: Jow
authors.forename: Mark
authors.initials: M
authors.lastname: Bowlby
authors.forename: Robert A
authors.initials: RA
authors.lastname: Crozier
authors.forename: Danni
authors.initials: D
authors.lastname: Liu
authors.forename: Shi
authors.initials: S
authors.lastname: Liang
authors.forename: Yi
authors.initials: Y
authors.lastname: Chen
authors.forename: Mary Lynn
authors.initials: ML
authors.lastname: Mercado
authors.forename: Xidong
authors.initials: X
authors.lastname: Feng
authors.forename: Frann
authors.initials: F
authors.lastname: Bennett
authors.forename: David
authors.initials: D
authors.lastname: von Schack
authors.forename: Leonard
authors.initials: L
authors.lastname: McDonald
authors.forename: Margaret M
authors.initials: MM
authors.lastname: Zaleska
authors.forename: Andrew
authors.initials: A
authors.lastname: Wood
authors.forename: Peter H
authors.initials: PH
authors.lastname: Reinhart
authors.forename: Ronald L
authors.initials: RL
authors.lastname: Magolda
authors.forename: Jerauld
authors.initials: J
authors.lastname: Skotnicki
authors.forename: Menelas N
authors.initials: MN
authors.lastname: Pangalos
authors.forename: Frank E
authors.initials: FE
authors.lastname: Koehn
authors.forename: Guy T
authors.initials: GT
authors.lastname: Carter
authors.forename: Magid
authors.initials: M
authors.lastname: Abou-Gharbia
authors.forename: Edmund I
authors.initials: EI
authors.lastname: Graziani
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000737:chemistry*; D004594:Electrophysiology / Q000379:methods; D006801:Humans; D020104:Immunophilins / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008024:Ligands; D008956:Models, Chemical; D016501:Neurites / Q000378:metabolism; D009447:Neuroblastoma / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D018408:Patch-Clamp Techniques; D011485:Protein Binding; D051381:Rats; D020123:Sirolimus / Q000737:chemistry*; D020521:Stroke / Q000378:metabolism; D022021:Tacrolimus Binding Proteins / Q000737:chemistry*
chemical_list: D015220:Calcium Channels; D007166:Immunosuppressive Agents; D008024:Ligands; D022021:Tacrolimus Binding Proteins; C403485:tacrolimus binding protein 4; D020104:Immunophilins; D002118:Calcium; D020123:Sirolimus