Signaling mechanisms of inhibition of phospholipase D activation by CHS-111 in formyl peptide-stimulated neutrophils

A selective phospholipase D (PLD) inhibitor 5-fluoro-2-indolyl des-chlorohalopemide (FIPI) inhibited the O 2 − generation and cell migration but not degranulation in formyl-Met-Leu-Phe (fMLP)-stimulated rat neutrophils. A novel benzyl indazole compound 2-benzyl-3-(4-hydroxymethylphenyl)indazole (CHS...

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Bibliographic Details
Published in:Biochemical pharmacology 2011-01, Vol.81 (2), p.269-278
Main Authors: Chang, Ling-Chu, Huang, Tai-Hung, Chang, Chi-Sen, Tsai, Ya-Ru, Lin, Ruey-Hseng, Lee, Pin-Wen, Hsu, Mei-Feng, Huang, Li-Jiau, Wang, Jih-Pyang
Format: Article
Language:English
Subjects:
ADP-Ribosylation Factors - genetics
ADP-Ribosylation Factors - metabolism
Animals
Arf6
Biological and medical sciences
Cardiac Myosins - genetics
Cardiac Myosins - metabolism
Carrier Proteins - genetics
Carrier Proteins - metabolism
Cell Degranulation - drug effects
cell free system
Cell Movement
CHS-111
Domperidone - analogs & derivatives
Domperidone - pharmacology
Enzyme Activation
guanine nucleotides
humans
Indazoles - pharmacology
Indoles - pharmacology
isozymes
Medical sciences
myosin light chains
Myosin Light Chains - genetics
Myosin Light Chains - metabolism
Neutrophils
Neutrophils - drug effects
pharmacology
Pharmacology. Drug treatments
Phospholipase D
Phospholipase D - antagonists & inhibitors
Phospholipase D - genetics
Phospholipase D - metabolism
phosphorylation
Phosphotransferases (Alcohol Group Acceptor) - genetics
Phosphotransferases (Alcohol Group Acceptor) - metabolism
Protein kinase C
Rats
Rats, Sprague-Dawley
Reactive Oxygen Species
recruitment
rho-Associated Kinases - genetics
rho-Associated Kinases - metabolism
RhoA
rhoA GTP-Binding Protein - genetics
rhoA GTP-Binding Protein - metabolism
Signal Transduction
Vav
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Summary:A selective phospholipase D (PLD) inhibitor 5-fluoro-2-indolyl des-chlorohalopemide (FIPI) inhibited the O 2 − generation and cell migration but not degranulation in formyl-Met-Leu-Phe (fMLP)-stimulated rat neutrophils. A novel benzyl indazole compound 2-benzyl-3-(4-hydroxymethylphenyl)indazole (CHS-111), which inhibited O 2 − generation and cell migration, also reduced the fMLP- but not phorbol ester-stimulated PLD activity (IC 50 3.9 ± 1.2 μM). CHS-111 inhibited the interaction of PLD1 with ADP-ribosylation factor (Arf) 6 and Ras homology (Rho) A, and reduced the membrane recruitment of RhoA in fMLP-stimulated cells but not in GTPγS-stimulated cell-free system. CHS-111 reduced the cellular levels of GTP-bound RhoA, membrane recruitment of Rho-associated protein kinase 1 and the downstream myosin light chain 2 phosphorylation, and attenuated the interaction between phosphatidylinositol 4-phosphate 5-kinase (PIP5K) and Arf6, whereas it only slightly inhibited the guanine nucleotide exchange activity of human Dbs (DH/PH) protein and did not affect the arfaptin binding to Arf6. CHS-111 inhibited the interaction of RhoA with Vav, the membrane association and the phosphorylation of Vav. CHS-111 had no effect on the phosphorylation of Src family kinases (SFK) but attenuated the interaction of Vav with Lck, Hck, Fgr and Lyn. CHS-111 also inhibited the interaction of PLD1 with protein kinase C (PKC) α, βI and βII isoenzymes, and the phosphorylation of PLD1. These results indicate that inhibition of fMLP-stimulated PLD activity by CHS-111 is attributable to the blockade of RhoA activation via the interference with SFK-mediated Vav activation, attenuation of the interaction of Arf6 with PLD1 and PIP5K, and the activation of Ca 2+-dependent PKC in rat neutrophils.
ISSN:0006-2952
1873-2968
DOI:10.1016/j.bcp.2010.10.007