The Protein Kinase C Inhibitors Bisindolylmaleimide I (GF 109203x) and IX (Ro 31-8220) Are Potent Inhibitors of Glycogen Synthase kinase-3 Activity

FEBS Lett. 1999 Nov 5;460(3):433-6. doi: 10.1016/s0014-5793(99)01389-7.

Abstract

Here we report that the widely used protein kinase C inhibitors, bisindolylmaleimide I and IX, are potent inhibitors of glycogen synthase kinase-3 (GSK-3). Bisindolylmaleimide I and IX inhibited GSK-3 in vitro, when assayed either in cell lysates (IC(50) 360 nM and 6.8 nM, respectively) or in GSK-3beta immunoprecipitates (IC(50) 170 nM and 2.8 nM, respectively) derived from rat epididymal adipocytes. Pretreatment of adipocytes with bisindolylmaleimide I (5 microM) and IX (2 microM) reduced GSK-3 activity in total cell lysates, to 25.1+/-4.3% and 12.9+/-3.0% of control, respectively. By contrast, bisindolylmaleimide V (5 microM), which lacks the functional groups present on bisindolylmaleimide I and IX, had little apparent effect. We propose that bisindolylmaleimide I and IX can directly inhibit GSK-3, and that this may explain some of the previously reported insulin-like effects on glycogen synthase activity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipocytes / drug effects
  • Adipocytes / enzymology
  • Animals
  • Calcium-Calmodulin-Dependent Protein Kinases / antagonists & inhibitors*
  • Cells, Cultured
  • Enzyme Activation / drug effects
  • Enzyme Inhibitors / pharmacology*
  • Glycogen Synthase Kinase 3
  • Glycogen Synthase Kinases
  • Indoles / pharmacology*
  • Male
  • Maleimides / pharmacology*
  • Microtubule-Associated Proteins / antagonists & inhibitors
  • Protein Kinase C / antagonists & inhibitors*
  • Rats
  • Rats, Wistar

Substances

  • Enzyme Inhibitors
  • Indoles
  • Maleimides
  • Microtubule-Associated Proteins
  • Glycogen Synthase Kinases
  • Protein Kinase C
  • Calcium-Calmodulin-Dependent Protein Kinases
  • Glycogen Synthase Kinase 3
  • bisindolylmaleimide I
  • Ro 31-8220