US EPA

8096369 

Journal Article 

Selective inhibition of protein kinase C isozymes by the indolocarbazole Go 6976 

Martiny-Baron, G; Kazanietz, MG; Mischak, H; Blumberg, PM; Kochs, G; Hug, H; Marme, D; Schachtele, C 

1993 

Yes 

Journal of Biological Chemistry
ISSN: 0021-9258
EISSN: 1083-351X 

268 

13 

9194-9197 

English 

Indolocarbazoles have been identified as novel inhibitors of protein kinase C (PKC), with Go 6976 as one of its most potent and selective representatives. Recombinant PKC isozymes α, β1, δ, ε, and ζ were used in in vitro kinase assays to investigate Go 6976 with respect to isozyme- specific PKC inhibition. Go 6850, identical with GF 109203X, another PKC- specific kinase inhibitor, was included in this study as a reference compound. Nanomolar concentrations of the indolocarbazole Go 6976 inhibited the Ca2+-dependent isozymes α and β1, whereas even micromolar concentration of Go 6976 had no effect on the kinase activity of the Ca2+- independent PKC subtypes δ, ε, and ζ. In contrast, the bisindolymaleimide Go 6850 inhibited all PKC isozymes, however, with a ranked order of potency (α > β1 > ε > δ > ζ). Kinetic analysis revealed that PKC inhibition by Go 6976 was competitive with respect to ATP, non-competitive with respect to the protein substrate, and mixed type with respect to phosphatidylserine. Further experiments in the presence of different amounts of free Ca2+ indicated that interference with Ca2+ or its binding site is not responsible for the differential inhibition of PKC isozymes by Go 6976.