Reversible Inhibition of Calcineurin by the Polyphenolic Aldehyde Gossypol

Ria Baumgrass, Matthias Weiwad, Frank Erdmann, Jun O. Liu, Dirk Wunderlich, Susanne Grabley, Gunter Fischer

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78 Scopus citations


The reversible inhibition of calcineurin (CAN)(CaN), which is the only Ca2+/calmodulin-dependent protein Ser/Thr phosphatase, is thought to be a key functional event for most cyclosporin A (CsA)- and tacrolimus (FK506)-mediated biological effects. In addition to CaN inhibition, however, CsA and FK506 have multiple biochemical effects because of their action in a gain-of-function model that requires prior binding to immunophilic proteins. We screened a small molecule library for direct inhibitors of CaN using CaN-mediated dephosphorylation of 33P-labeled 19-residue phosphopeptide substrate (RII phosphopeptide) as an assay and found the polyphenolic aldehyde gossypol to be a novel CaN inhibitor. Unlike CsA and FK506, gossypol does not require a matchmaker protein for reversible CaN inhibition with an IC50 value of 15 μM. Gossypolone, a gossypol analog, showed improved inhibition of both RII phosphopeptide and p-nitrophenyl phosphate dephosphorylation with an IC50 of 9 and 6 μM, respectively. In contrast, apogossypol hexaacetate was inactive. Gossypol acts noncompetitively, interfering with the binding site for the cyclophilin 18-CsA complex in CaN. In contrast to CsA and FK506, gossypol does not inactivate the peptidyl-prolyl-cis/trans-isomerase activity of immunophilins. Similar to CsA and FK506, T cell receptor signaling induced by phorbol 12-myristate 13-acetate/ionomycin is inhibited by gossypol in a dose-dependent manner, demonstrated by the inhibition of nuclear factor of activated T cell (NFAT) cl translocation from the cytosol into the nucleus and suppression of NFAT-luciferase reporter gene activity.

Original languageEnglish (US)
Pages (from-to)47914-47921
Number of pages8
JournalJournal of Biological Chemistry
Issue number51
StatePublished - Dec 21 2001

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology


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