title: Non-specific effects of 4-chloro-m-cresol may cause calcium flux and respiratory burst in human neutrophils.
abstract: We examined the effects of 4-chloro-m-cresol (4-CmC, a potent and specific activator of ryanodine receptors) on Ca(2+)-release/influx and respiratory burst in freshly isolated human PMN as well as HL60 cells. 4-CmC induces Ca(2+) store-depletion in a dose-dependent manner at concentrations between 400muM and 3mM, however no dose-dependent effect on Ca(2+)-influx was found. 4-CmC depleted Ca(2+) stores that were shared with the GPC agonists such as fMLP and PAF, and therefore 4-CmC presumably depletes Ca(2+) from ER. Since the authentic ligand for RyR is cyclic ADP-ribose (cADPR), we assessed the functional relevance of RyR in PMN by studying the presence and function of membrane-bound ADP-ribosyl cyclase (CD38) in PMN. First, expression of CD38 was confirmed by RT-PCR using cDNA from HL60 cells. Second, PMN from trauma patients showed significantly enhanced CD38 expression than those from healthy volunteers. In addition, although no chemotaxis effect was detected by 4-CmC, it stimulated respiratory burst in PMN in a dose-dependent manner. Our findings suggest that RyRs exist in human PMN and that RyR pathway may play an active role in inflammatory PMN calcium signaling. 8-Br-cADPR and cyclic 3-deaza-ADP did not have inhibitory effects either on 4-CmC-induced Ca(2+) store-depletion or on respiratory burst, on the other hand, PLC inhibitor, U73122, completely attenuated both 4-CmC-induced Ca(2+) store-depletion and respiratory burst. Although it has been used as a specific activator of RyR, 4-CmC has non-specific effects which cause Ca(2+) store-depletion and respiratory burst at least in human PMN.
authors.affiliation: The Department of Surgery, Division of Trauma, UMDNJ-New Jersey Medical School, Newark, 07103, USA.
authors.forename: Carl J
authors.initials: CJ
authors.lastname: Hauser
authors.forename: Kolenkode B
authors.initials: KB
authors.lastname: Kannan
authors.forename: Edwin A
authors.initials: EA
authors.lastname: Deitch
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Itagaki
mesh_terms: D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology*; D003408:Cresols / Q000494:pharmacology*; D036563:Cyclic ADP-Ribose / Q000378:metabolism; D004963:Estrenes / Q000494:pharmacology; D018922:HL-60 Cells; D006801:Humans; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology*; D010972:Platelet Activating Factor / Q000502:physiology; D011760:Pyrrolidinones / Q000494:pharmacology; D016897:Respiratory Burst / Q000187:drug effects*; D019837:Ryanodine Receptor Calcium Release Channel / Q000187:drug effects* / Q000378:metabolism; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D002121:Calcium Channel Blockers; D003408:Cresols; D004963:Estrenes; D010972:Platelet Activating Factor; D011760:Pyrrolidinones; D019837:Ryanodine Receptor Calcium Release Channel; C060229:1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione; D036563:Cyclic ADP-Ribose; C006984:chlorocresol; D009240:N-Formylmethionine Leucyl-Phenylalanine; D010738:Type C Phospholipases; D002118:Calcium