title: Calpain inhibitors stimulate phagocyte functions via activation of human formyl peptide receptors.
abstract: Calpain inhibitors induce pertussis toxin (PTx)-sensitive chemotaxis in human neutrophils and monocytes. Here, we show that various calpain inhibitors (PD150606, PD151746, N-acetyl-Leu-Leu-Nle-CHO [ALLN], N-acetyl-Leu-Leu-Met-CHO [ALLM], and calpeptin) and γ-secretase inhibitor I induced PTx-sensitive increase in cytoplasmic free Ca(2+) ([Ca(2+)](i)) in human neutrophils and neutrophil migration. HEK-293 cells stably expressing human formyl peptide receptor (hFPR) or hFPR-like 1 (hFPRL1) displayed stimulus-specific increase in [Ca(2+)](i) in response to calpain inhibitors (PD150606, PD151746, ALLN, ALLM, MG-132, and calpeptin), γ-secretase inhibitor I, and N-formyl-Met-Leu-Phe. Parent HEK-293 cells also displayed PTx-sensitive increase in [Ca(2+)](i) in response to calpeptin and γ-secretase inhibitor I, whereas they displayed PTx-resistant increase in [Ca(2+)](i) in response to MG-132. MDL-28170 induced neither an increase in [Ca(2+)](i) in neutrophils and HEK-293 cells nor neutrophil migration. Ionomycin-induced cleavage of talin (a substrate of calpain) in neutrophils was inhibited by all inhibitors used here. These findings suggest that potent calpain inhibitors could stimulate phagocyte functions via activation of hFPR, hFPRL1 and/or other G-protein coupled receptors depending on the inhibitors used.
authors: Department of Physiology, Osaka City University, Graduate School of Medicine, Asahi-machi, Abeno-ku, Osaka, Japan.
authors: Hisakazu
authors: H
authors: Fujita
authors: Takayuki
authors: T
authors: Kato
authors: Norifumi
authors: N
authors: Watanabe
authors: Tatsuji
authors: T
authors: Takahashi
authors: Seiichi
authors: S
authors: Kitagawa
mesh_terms: D002118:Calcium / Q000378:metabolism; D002154:Calpain / Q000037:antagonists & inhibitors*; D002633:Chemotaxis / Q000187:drug effects* / Q000502:physiology; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D009000:Monocytes / Q000166:cytology / Q000378:metabolism*; D009504:Neutrophils / Q000166:cytology / Q000378:metabolism*; D044042:Receptors, Formyl Peptide / Q000235:genetics / Q000378:metabolism*; D044067:Receptors, Lipoxin / Q000235:genetics / Q000378:metabolism*
chemical_list: D015853:Cysteine Proteinase Inhibitors; C469986:FPR1 protein, human; C105101:FPR2 protein, human; D044042:Receptors, Formyl Peptide; D044067:Receptors, Lipoxin; D002154:Calpain; D002118:Calcium