Circulation Research. 2002;91:398-405
Published online before print August 15, 2002, doi: 10.1161/01.RES.0000033520.95242.A2
Published online before print August 15, 2002, doi: 10.1161/01.RES.0000033520.95242.A2
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© 2002 American Heart Association, Inc.
Molecular Medicine |
G
q and Gß
Regulate PAR-1 Signaling of Thrombin-Induced NF-
B Activation and ICAM-1 Transcription in Endothelial Cells
From the Department of Pharmacology, College of Medicine, The University of Illinois, Chicago, Ill.
Correspondence to Arshad Rahman, Dept of Pharmacology, The University of Illinois, College of Medicine, 835 South Wolcott Ave (M/C 868), Chicago, IL 60612-7343. E-mail ARahman{at}uic.edu
As thrombin binding to the G protein–coupled proteinase activated receptor-1 (PAR-1) induces endothelial adhesivity to leukocytes through NF-
B activation and intercellular adhesion molecule-1 (ICAM-1) expression, we determined the signaling pathways mediating the response. Studies showed that the heterotrimeric G proteins, G
q, and the Gß
dimer were key determinants of the PAR-1 agonist peptide (TFLLRNPNDK)-induced NF-B activation and ICAM-1 expression in endothelial cells. Cotransfection of RGS3T, a regulator of G-protein signaling that inhibits Gq, or -transducin (Gt), a scavenger of the Gß, markedly decreased NF-B activity induced by PAR-1 activation. We determined the downstream signaling targets activated by Gq and Gß that mediate NF-B activation. Expression of the kinase-defective protein kinase C (PKC)-
mutant inhibited NF-B activation induced by the constitutively active Gq mutant, but had no effect on NF-B activity induced by Gß12. In related experiments, NF-B as well as ICAM-1 promoter activation induced by Gß12 were inhibited by the expression of the dominant-negative mutant of 85-kDa regulatory subunit of PI 3-kinase; however, the expression of this mutant had no effect on the response induced by activated Gq. Cotransfection of the catalytically inactive Akt mutant inhibited the NF-B activation induced by the constitutively active PI 3-kinase mutant as well as that by the activated forms of Gq and PKC-. These results support a model in which ligation of PAR-1 induces NF-B activation and ICAM-1 transcription by the engagement of parallel Gq/PKC- and Gß/PI3-kinase pathways that converge at Akt.
Key Words: G proteins • protein kinase C- • Akt • nuclear factor-B • intercellular adhesion molecule-1
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