Bisindolylmaleimide I

"目录号: HY-13867

EpigeneticsTGF-beta/Smad-

Bisindolylmaleimide I (GF109203X) 是一种具有高度选择性，细胞可渗透性和可逆性的PKC抑制剂,Ki值为14 nM。

PKC

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生物活性

Description

Bisindolylmaleimide I (GF109203X) is a highly selective, cell-permeable, and reversible protein kinase C (PKC) inhibitor with aKiof 14 nM.

IC50& Target

Ki: 20±7 nM (PKC α); 17±5 nM (PKC βI); 16±5 nM (PKC βII); 20±5 nM (PKC γ)[1]

In Vitro

Bisindolylmaleimide I  is a competitive inhibitor with respect to ATP (Ki=14 nM) and displays high selectivity for PKC as compared to five different protein kinases. GF 109203X efficiently prevents PKC-mediated phosphorylations of an Mr=47,000 protein in platelets and of an Mr=80,000 protein in Swiss 3T3 cells. GF 109203X inhibits collagen- and a-thrombin-induced platelet aggregation as well as collagen-triggered ATP secretion. However, ADP-dependent reversible aggregation is not modified. In Swiss 3T3 fibroblasts, GF 109203X reverses the inhibition of epidermal growth factor binding induced by phorbol 12,13-dibutyrate and prevents [3H] thymidine incorporation into DNA, only when this is elicited by growth promoting agents which activate PKC[1].

In Vivo

Pial arteriole diameter changes are monitored using a closed cranial windowin vivomicroscopy technique. The pial arteriole dilatory response associated with SNS is decreased by 45%, when comparing DM vs either ND or TR rats. Also, pial arteriolar dilations to topical KCl and NS1619 are largely attenuated in DM rats, but not in ND or TR animals. These responses are completely restored by the acute application of Bisindolylmaleimide I  to the brain surface. The PKC inhibitor has no effect on vascular responses in normoglycemic and TR animals. In conclusion, DM-associated chronic impairment of neurovascular coupling may be readily reversed by a PKC-α/β/γ inhibitor or prevented via pancreatic islet transplantation. Specific PCK isoforms (α/β/γ) are believed to be mechanistically linked to the neurovascular uncoupling seen with hyperglycemia[2].

References

[1].Toullec D, et al. The bisindolylmaleimide GF 109203X is a potent and selective inhibitor of protein kinase C. J Biol Chem. 1991 Aug 25;266(24):15771-81.

[2].Vetri F, et al. Impairment of neurovascular coupling in Type 1 Diabetes Mellitus in rats is prevented by pancreatic islet transplantation and reversed by a semi-selective PKC inhibitor. Brain Res. 2017 Jan 15;1655:48-54.