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MEMBRANE TRANSPORTERS, ION CHANNELS, AND PUMPS

Prostaglandin E₂ activates outwardly rectifying Cl^– channels via a cAMP-dependent pathway and reduces cell motility in rat osteoclasts

Department of Physiological Science and Molecular Biology, Fukuoka Dental College, Fukuoka 814-0193, Japan

Submitted 4 December 2003 ; accepted in final form 17 March 2004

We examined changes in electrical and morphological properties of rat osteoclasts in response to prostaglandin (PG)E₂. PGE₂ (>10 nM) stimulated an outwardly rectifying Cl^– current in a concentration-dependent manner and caused a long-lasting depolarization of cell membrane. This PGE₂-induced Cl^– current was reversibly inhibited by 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS), 5-nitro-2-(3-phenylpropylamino)-benzoic acid (NPPB), and tamoxifen. The anion permeability sequence of this current was I^– > Br^– Cl^– > gluconate^–. When outwardly rectifying Cl^– current was induced by hyposmotic extracellular solution, no further stimulatory effect of PGE₂ was seen. Forskolin and dibutyryl adenosine 3',5'-cyclic monophosphate (DBcAMP) mimicked the effect of PGE₂. The PGE₂-induced Cl^– current was inhibited by pretreatment with guanosine 5'-O-2-(thiodiphosphate) (GDPS), Rp-adenosine 3',5'-cyclic monophosphorothioate (Rp-cAMPS), N-(2-[p-bromocinnamylamino]ethyl)-5-isoquinolinesulfonamide dihydrochloride (H-89), and protein kinase A inhibitors. Even in the absence of nonosteoclastic cells, PGE₂ (1 µM) reduced cell surface area and suppressed motility of osteoclasts, and these effects were abolished by Rp-cAMPS or H-89. PGE₂ is known to exert its effects through four subtypes of PGE receptors (EP1–EP4). EP2 and EP4 agonists (ONO-AE1-259 and ONO-AE1-329, respectively), but not EP1 and EP3 agonists (ONO-DI-004 and ONO-AE-248, respectively), mimicked the electrical and morphological actions of PGE₂ on osteoclasts. Our results show that PGE₂ stimulates rat osteoclast Cl^– current by activation of a cAMP-dependent pathway through EP2 and, to a lesser degree, EP4 receptors and reduces osteoclast motility. This effect is likely to reduce bone resorption.

prostanoid receptor agonists; electrophysiology; motile activity; bone resorption

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