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J. Biol. Chem., Vol. 276, Issue 42, 39107-39114, October 19, 2001
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From the Canadian Institutes of Health Research Group in
Skeletal Development and Remodeling, Department of Physiology and
Division of Oral Biology, Faculty of Medicine and Dentistry, The
University of Western Ontario, London, Ontario N6A 5C1, Canada
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 P2X7
antagonist. 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.
Activity-dependent Development of
P2X7 Current and Ca2+ Entry in Rabbit
Osteoclasts*
*
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.
To whom correspondence should be addressed. Tel.:
519-661-3768; Fax: 519-661-3827; E-mail:
stephen.sims@fmd.uwo.ca.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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