Binding of rapamycin analogs to calcium channels and FKBP52 contributes to their neuroprotective activities.
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.
Ruan
Benfang
B
Chemical and Screening Sciences, Wyeth Research, 401 North Middletown Road, Pearl River, NY 10965, USA.
Pong
Kevin
K
Jow
Flora
F
Bowlby
Mark
M
Crozier
Robert A
RA
Liu
Danni
D
Liang
Shi
S
Chen
Yi
Y
Mercado
Mary Lynn
ML
Feng
Xidong
X
Bennett
Frann
F
von Schack
David
D
McDonald
Leonard
L
Zaleska
Margaret M
MM
Wood
Andrew
A
Reinhart
Peter H
PH
Magolda
Ronald L
RL
Skotnicki
Jerauld
J
Pangalos
Menelas N
MN
Koehn
Frank E
FE
Carter
Guy T
GT
Abou-Gharbia
Magid
M
Graziani
Edmund I
EI
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*
D015220:Calcium Channels; D007166:Immunosuppressive Agents; D008024:Ligands; D022021:Tacrolimus Binding Proteins; C403485:tacrolimus binding protein 4; D020104:Immunophilins; D002118:Calcium; D020123:Sirolimus