Stimulation of intracellular Ca²⁺ elevation in neutrophils by thiol-oxidizing phenylarsine oxide

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• 作者：Wang ; Jih-Pyang ; Tsai ; Jaw-Ji ; Chen ; Yu-San ; Hsu ; Mei-Feng
• 关键词：Phenylarsine oxide ; Cation entry ; Intracellular free-Ca²⁺ ; Signal transduction ; Non-store operated Ca²⁺ entry ; Neutrophils
• 刊名：Biochemical Pharmacology
• 出版年：2005
• 出版时间：April 15, 2005
• 年：2005
• 卷：69
• 期：8
• 页码：1225-1234
• 全文大小：281 K

文摘

Phenylarsine oxide (PAO), a trivalent arsenical compound, stimulated [Ca²⁺]_i elevation in rat neutrophils in a Ca²⁺-containing medium but caused no appreciable response in a Ca²⁺-free medium. PAO also induced external Mn²⁺ entry, which was inhibited by N-acetyl-l-cysteine (NAC), but failed to elicit any appreciable Ba²⁺ and Sr²⁺ entry. Pretreatment of neutrophils with thiol-reducing agents including dithiothreitol (DTT), NAC, 2,3-dimercapto-1-propanol (DMP), 2,3-dimercaptopropane-1-sulfonic acid (DMPS) and tris-(2-carboxyethyl)phosphine (TCEP), all greatly inhibited PAO-induced [Ca²⁺]_i elevation. Addition of Ni²⁺ or La³⁺ followed by PAO stimulation also attenuated the Ca²⁺ signals in a concentration-dependent manner. PAO had no significant effect on the production of reactive oxygen intermediates (ROI) and nitric oxide (NO) nor did it decrease cellular low molecular weight thiols levels. PAO-induced [Ca²⁺]_i elevation was significantly inhibited by 1-[6-[17β-3-methoxyestra-1,3,5(10)-trien-17-yl]amino]hexyl]-1H-pyrrole-2,5-dione (U-73122), the inhibitor of phospholipase C-coupled processes, genistein, a general tyrosine kinase inhibitor, phorbol 12-myristate 13-acetate (PMA), a protein kinase C (PKC) activator, calyculin A, a cortical actin stabilizer, 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY 294002), a phosphoinositide 3-kinase inhibitor, 1-[β-[3-(4-methoxyphenyl)propoxy]-4-methoxyphenethyl]-1H-imidazole (SKF-96365), and cis-N-(2-phenylcyclopentyl)azacyclotridec-1-en-2-amine (MDL-12,330A), the blockers of receptor-gated and store-operated Ca²⁺ channels, whereas there was no appreciable effect exerted by aristolochic acid, a phospholipase A₂ inhibitor, 7-nitroindazole and N-(3-aminomethyl)benzylacetamidine (1400W), the blockers of NO synthase, and by suspension in a Na⁺-deprived medium. In contrast, 2-aminoethoxydiphenyl borane (2-APB), the blocker of IP₃ receptor and Ca²⁺ influx, enhanced the PAO-induced response. PAO had no effect on the plasma membrane Ca²⁺-ATPase (PMCA) activity in the pharmacological isolated neutrophil preparation and the neutrophil membrane fractions. These results indicate that PAO stimulates [Ca²⁺]_i rise in rat neutrophils mainly through the oxidation of vicinal thiol groups on the cell surface membrane to activation of a non-store operated Ca²⁺ entry (non-SOCE) without affecting the activity of PMCA and the plasmalemmal Na⁺/Ca²⁺ exchanger.