Journal
AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY
Volume 290, Issue 2, Pages G250-G261Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpgi.00501.2004
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- NIDDK NIH HHS [R01 DK-44571] Funding Source: Medline
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During acute exacerbations of inflammatory bowel diseases, oxidants are generated through the interactions of bacteria in the lumen, activated granulocytes, and cells of the colon mucosa. In this study we explored the ability of one such class of oxidants, represented by monochloramine (NH2Cl), to serve as agonists of Ca2+ and Zn2+ accumulation within the colonocyte. Individual colon crypts prepared from Sprague-Dawley rats were mounted in perfusion chambers after loading with fluorescent reporters fura 2-AM and fluozin 3-AM. These reporters were characterized, in situ, for responsiveness to Ca2+ and Zn2+ in the cytoplasm. Responses to different concentrations of NH2Cl ( 50, 100, and 200 mu M) were monitored. Subsequent studies were designed to identify the sources and mechanisms of NH2Cl-induced increases in Ca2+ and Zn2+ in the cytoplasm. Exposure to NH2Cl led to dose-dependent increases in intracellular Ca2+ concentration ([Ca2+](i)) in the range of 200 - 400 nM above baseline levels. Further studies indicated that NH2Cl-induced accumulation of Ca2+ in the cytoplasm is the result of release from intracellular stores and basolateral entry of extracellular Ca2+ through store-operated channels. In addition, exposure to NH2Cl resulted in dose-dependent and sustained increases in intracellular Zn2+ concentration ([Zn2+](i)) in the nanomolar range. These alterations were neutralized by dithiothreitol, which shields intracellular thiol groups from oxidation. We conclude that Ca2+- and Zn2+- handling proteins are susceptible to oxidation by chloramines, leading to sustained, but not necessarily toxic, increases in [Ca2+](i) and [Zn2+](i). Under certain conditions, NH2Cl may act not as a toxin but as an agent that activates intracellular signaling pathways.
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