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Mol Pharmacol. 2008 Feb;73(2):410-8. Epub 2007 Nov 15.

Small molecule disruption of G protein beta gamma subunit signaling inhibits neutrophil chemotaxis and inflammation.

Author information

1
University of Rochester, Department of Pharmacology and Physiology, 601 Elmwood Ave., Box 711, Rochester, NY 14642, USA.

Abstract

G protein betagamma subunit-dependent signaling is important for chemoattractant-dependent leukocyte chemotaxis. Selective small molecule targeting of phosphoinositide 3-kinase (PI3-kinase) gamma catalytic activity is a target of interest for anti-inflammatory pharmaceutical development. In this study, we examined whether small-molecule inhibition of Gbetagamma-dependent signaling, including Gbetagamma-dependent activation of PI3-kinase gamma and Rac1, could inhibit chemoattractant-dependent neutrophil migration in vitro and inflammation in vivo. Small-molecule Gbetagamma inhibitors suppressed fMLP-stimulated Rac activation, superoxide production, and PI3-kinase activation in differentiated HL60 cells. These compounds also blocked fMLP-dependent chemotaxis in HL60 cells and primary human neutrophils. Systemic administration inhibited paw edema and neutrophil infiltration in a mouse carrageenan-induced paw edema model. Overall, the data demonstrate that targeting Gbetagamma-regulation may be an effective anti-inflammation strategy.

PMID:
18006643
PMCID:
PMC2742223
DOI:
10.1124/mol.107.041780
[Indexed for MEDLINE]
Free PMC Article

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