Small G-proteins Ras,Rac and Rho in the regulation of the neutrophil respiratory burst induced by formyl peptide |
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Authors: | Yu V Filina V G Safronova A G Gabdoulkhakova |
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Institution: | 1.Kazan State Medical Academy,Kazan,Russia;2.Institute of Cell Biophysics,Russian Academy of Sciences,Pushchino, Moscow oblast,Russia |
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Abstract: | Formylated peptides specifically activate many of the neutrophil functions; their action is mediated via formyl peptide receptors
(FPRs). FPRs belong to the family of receptors having seven transmembrane-spanning domains and coupled with G-proteins (GPCR).
About a dozen of highly homologous genes of FPRs were found to be localized in mouse chromosome 17. By binding with labeled
N-formyl-Met-Leu-Phe (fMLF), FPRs are classified as receptors with high (FPR1) and low (FPR2 and FPR3/FPRL1) affinity to formyl
peptide. Binding of formyl peptide with FPRs triggers the complex signaling events, the most studied are: activation of phospholipase
C (PLC) with subsequent calcium signaling; launching of mitogen activated protein kinases (MAPKs) cascade pathway, and activation
of phosphoinositol-3-kinase (PI3K) cascades. As we have shown previously, the priming of the respiratory burst of mice neutrophils
occurs under the cell activation by fMLF in high doses only, i.e., it is necessary to activate low affinity FPRs. Besides,
the usage of the specific MEK and p38MAPK inhibitors induced significant suppression of the response to 1 μM fMLM, while the
response to 50 μM fMLF increased in the presence of the inhibitors. We suggest that there is a signal divergence upon activation
of high and low affinity fMLF receptors, and small G protein dependent signaling pathways could be alternative to activate
NADPH oxidase. Here we demonstrate that Ras-proteins participate in the respiratory burst activation, especially in activation
via the high affinity fMLF receptors. Activation of the Rho- and Rac-proteins induced the down-regulation of the respiratory
burst under the stimulation of high affinity FPRs. The inhibition of the Rho-proteins almost completely suppressed the respiratory
burst activated via the high and low affinity receptors, probably due to inability to assemble of the cytoskeleton proteins
and NADPH oxidase components. |
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