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

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 M

doi

10.1073/pnas.0710424105

subject

Has Abstract

pub_date

2008-01-08 00:00:00

pages

33-8

issue

1

eissn

0027-8424

issn

1091-6490

pii

0710424105

journal_volume

105

pub_type

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