Journal of Biological Chemistry
Volume 276, Issue 42, 19 October 2001, Pages 39107-39114
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MECHANISMS OF SIGNAL TRANSDUCTION
Activity-dependent Development of P2X7 Current and Ca2+ Entry in Rabbit Osteoclasts*

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Bone remodeling is regulated by local factors and modulated by mechanical stimuli. Mechanical stimulation can cause release of ATP, an agent that stimulates osteoclastic resorption at low concentrations and inhibits at high concentrations. We examined whether osteoclasts express P2X7 receptors, which are activated by high concentrations of ATP and can behave as ion channels or cause the formation of membrane pores. Rabbit osteoclasts were studied using patch clamp techniques. Successive or prolonged applications of 2′- & 3′-O-(4-benzoylbenzoyl)-ATP (BzATP, a relatively potent P2X7 agonist) or high concentrations of ATP caused the development of a slowly deactivating inward current. The underlying channel was permeable only to small cations, ruling out pore formation. Divalent cations reduced current magnitude, consistent with the presence of P2X7 receptors, a finding confirmed in rat osteoclasts by immunocytochemistry. Successive applications of BzATP also elicited [Ca2+]i elevations that required extracellular Ca2+. The BzATP-induced current and the rise of [Ca2+]i were temporally associated, and both were inhibited by PPADS, a P2X7antagonist. This study demonstrates that high concentrations of ATP activate P2X7 receptors and provides the first functional evidence for an extracellular ligand-gated Ca2+ influx pathway in osteoclasts. ATP released in response to mechanical stimuli may act through P2X7 receptors to inhibit osteoclastic resorption.

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Published, JBC Papers in Press, August 8, 2001, DOI 10.1074/jbc.M105881200

*

This work was supported by The Arthritis Society and the Canadian Arthritis Network.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.