Sci. Signal., 15 January 2008
Pharmacology Targeting Immunophilins for Neuroprotection
Nancy R. Gough
Science Signaling, AAAS, Washington, DC 20005, USA
Immunophilins are a family of proteins with peptidyl-prolyl isomerase activity that are the target of a class of immunosuppressive drugs that include FK506 and rapamycin (immunophilins are named FKBPs for FK506-binding proteins). Although initially characterized for their role in regulation of immune responses, this large family of proteins (>24 in humans) regulates a large array of targets and is implicated in various biological processes. Immunophilin ligands have been reported to act as neuroprotective agents, but their usefulness has been limited by off-target effects such as immunosuppression mediated by interference in the mTOR pathway through interactions with FKBP12 or cardiac dysfunction mediated by interference with excitation-contraction coupling through interactions with FKBP12.6. Ruan et al. chemically modified rapamycin and generated two compounds, WYE-592 and ILS-920, that lacked immunosuppressive activity (based on a T cell proliferation assay) yet retained the ability to promote survival and neurite outgrowth of cultured cortical neurons and F-11 cells (a rat neuron and mouse neuroblastoma hybrid cell line). Affinity purification assays with lysates from F-11 cells indicated that these compounds bound to FKBP52, which regulates steroid receptor activity, and to the β1 subunit of the L-type voltage-gated calcium channel (VGCC). WYE-592 and ILS-920 exhibited much higher affinity binding for FKBP52 than for FKBP12. The binding to the β subunit of the VGCC was selective for the β1 subunit and occurred with purified protein in the absence of FKBP proteins, which suggests a direct interaction. However, WYE-592 promoted an interaction between FKBP52 and the VGCC β1 subunit, which did not occur in the absence of the drug (based on coimmunoprecipitation experiments with F-11 cells). It appeared that the effects on neuronal survival and neurite outgrowth were mediated through different mechanisms. Only knockdown of FKBP52 with RNA interference techniques promoted neurite outgrowth of cortical neurons, whereas knockdown of the β1 subunit had no effect. Instead, in cultured hippocampal neurons and F-11 cells, the drugs inhibited VGCC activity (based on ion electrophysiological analysis of calcium currents), potentially limiting neurotoxic calcium accumulation. It remains to be determined whether inhibition requires FKBP52. In a rodent model of stroke, administration of ILS-920 reduced the size of the infarct. Thus, these drugs provide promise that selective immunophilin ligands can be synthesized that limit off-target effects and identify a target, the VGCC, that may have an important role in the neuroprotective effects of these drugs.
B. Ruan, K. Pong, F. Jow, M. Bowlby, R. A. Crozier, D. Liu, S. Liang, Y. Chen, M. L. Mercado, X. Feng, F. Bennett, D. von Schack, L. McDonald, M. M. Zaleska, A. Wood, P. H. Reinhart, R. L. Magolda, J. Skotnicki, M. N. Pangalos, F. E. Koehn, G. T. Carter, M. Abou-Gharbia, E. I. Graziani, Binding of rapamycin analogs to calcium channels and FKBP52 contributes to their neuroprotective activities. Proc. Natl. Acad. Sci. U. S. A. 105, 33-38 (2008). [Abstract] [Full Text]
Citation: N. R. Gough, Targeting Immunophilins for Neuroprotection. Sci. Signal. 1, ec18 (2008).
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