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1 Department of Physiology and Biophysics, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106; and 2 Serono Pharmaceutical Research Institute, Geneva, Switzerland
P2X
receptors function as ATP-gated cation channels. The P2X7
receptor subtype is distinguished from other P2X family members by a
very low affinity for extracellular ATP (millimolar EC50) and its ability to trigger induction of nonselective pores on repeated
or prolonged stimulation. Previous studies have indicated that certain
P2X7 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
P2X7 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 P2X7
receptors. Comparison of P2X7 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 P2X7 receptor
protein at the cell surface of macrophages. Thus ability of ATP to
activate nonselective pores in cells that natively express
P2X7 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
P2X7 receptor activation in monocytes until these
proinflammatory leukocytes migrate to extravascular sites of tissue damage.
macrophage; extracellular ATP; inflammation; ligand-gated ion channel
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