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Regulation of P2X 7 nucleotide receptor function in human monocytes by extracellular ions and receptor density

P2X receptors function as ATP-gated cation channels. The P2X 7 receptor subtype is distinguished from other P2X family members by a very low affinity for extracellular ATP (millimolar EC 50 ) and its ability to trigger induction of nonselective pores on repeated or prolonged stimulation. Previous st...

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Bibliographic Details
Published in:American Journal of Physiology: Cell Physiology 2001-04, Vol.280 (4), p.C943-C953
Main Authors: Gudipaty, Lalitha, Humphreys, Benjamin D., Buell, Gary, Dubyak, George R.
Format: Article
Language:English
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Summary:P2X receptors function as ATP-gated cation channels. The P2X 7 receptor subtype is distinguished from other P2X family members by a very low affinity for extracellular ATP (millimolar EC 50 ) and its ability to trigger induction of nonselective pores on repeated or prolonged stimulation. Previous studies have indicated that certain P2X 7 receptor-positive cell types, such as human blood monocytes and murine thymocytes, lack this pore-forming response. In the present study we compared pore formation in response to P2X 7 receptor activation in human blood monocytes with that in macrophages derived from these monocytes by in vitro tissue culture. ATP induced nonselective pores in macrophages but not in freshly isolated monocytes when both cell types were identically stimulated in standard NaCl-based salines. However, ion substitution studies revealed that replacement of extracellular Na + and Cl − with K + and nonhalide anions strongly facilitated ATP-dependent pore formation in monocytes. These ionic conditions also resulted in increased agonist affinity, such that 30–100 μM ATP was sufficient for activation of nonselective pores by P2X 7 receptors. Comparison of P2X 7 receptor expression in blood monocytes with that in macrophages indicated no differences in steady-state receptor mRNA levels but significant increases (up to 10-fold) in the amount of immunoreactive P2X 7 receptor protein at the cell surface of macrophages. Thus ability of ATP to activate nonselective pores in cells that natively express P2X 7 receptors can be modulated by receptor subunit density at the cell surface and ambient levels of extracellular Na + and Cl − . These mechanisms may prevent adventitious P2X 7 receptor activation in monocytes until these proinflammatory leukocytes migrate to extravascular sites of tissue damage.
ISSN:0363-6143
1522-1563
DOI:10.1152/ajpcell.2001.280.4.C943