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Study of synthetic peptides derived from the PKI55 protein, a protein kinase C modulator, in human neutrophils stimulated by the methyl ester derivative of the hydrophobic N-formyl tripeptide for-Met-Leu-Phe-OH.
- Source :
-
The FEBS journal [FEBS J] 2008 Feb; Vol. 275 (3), pp. 449-57. Date of Electronic Publication: 2007 Dec 21. - Publication Year :
- 2008
-
Abstract
- Elucidation of the involvement of protein kinase C subtypes in several diseases is an important challenge for the future development of new drug targets. We previously identified the PKI55 protein, which acts as a protein kinase C modulator, establishing a feedback loop of inhibition. The PKI55 protein is able to penetrate the cell membrane of activated human T-lymphocytes and to inhibit the activity of alpha, beta(1) and beta(2) protein kinase C isoforms. The present study aimed to identify the minimal amino acid sequence of PKI55 that is able to inhibit the enzyme activity of protein kinase C. Peptides derived from both C- and N-terminal sequences were synthesized and initially assayed in rat brain protein kinase C to identify which part of the entire protein maintained the in vitro effects described for PKI55, and then the active peptides were tested on the isoforms alpha, beta(1), beta(2), gamma, delta, epsilon and zeta to identify their specific inhibition properties. Specific protein kinase C isoforms have been associated with the activation of specific signal transduction pathways involved in inflammatory responses. Thus, the potential therapeutic role of the selected peptides has been studied in polymorphonuclear leukocytes activated by the methyl ester derivative of the hydrophobic N-formyl tripeptide for-Met-Leu-Phe-OH to evaluate their ability to modulate chemotaxis, superoxide anion production and lysozyme release. These studies have shown that only chemotactic function is significantly inhibited by these peptides, whereas superoxide anion production and lysozyme release remain unaffected. Western blotting experiments also demonstrated a selective reduction in the levels of the protein kinase C beta(1) isoform, which was previously demonstrated to be associated with the polymorphonuclear leukocyte chemotactic response.
- Subjects :
- Amino Acid Sequence
Animals
Blotting, Western
Brain drug effects
Brain metabolism
Cell Survival drug effects
Enzyme Activation drug effects
Humans
Hydrophobic and Hydrophilic Interactions
Isoenzymes antagonists & inhibitors
Isoenzymes metabolism
Molecular Sequence Data
Muramidase metabolism
N-Formylmethionine Leucyl-Phenylalanine chemistry
Neutrophils cytology
Neutrophils metabolism
Peptides chemical synthesis
Peptides chemistry
Protein Kinase C metabolism
Protein Kinase C beta
Proteins chemistry
Rats
Superoxides metabolism
N-Formylmethionine Leucyl-Phenylalanine pharmacology
Neutrophils drug effects
Peptides pharmacology
Protein Kinase C antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1742-464X
- Volume :
- 275
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- The FEBS journal
- Publication Type :
- Academic Journal
- Accession number :
- 18167144
- Full Text :
- https://doi.org/10.1111/j.1742-4658.2007.06212.x