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

Fujio Okamoto, Hiroshi Kajiya, Hidefumi Fukushima, Eijiro Jimi, Koji Okabe

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16 Citations (Scopus)

Abstract

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) (GDPβS), 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.

Original languageEnglish
Pages (from-to)C114-C124
JournalAmerican Journal of Physiology - Cell Physiology
Volume287
Issue number1 56-1
DOIs
Publication statusPublished - 2004 Jul

Keywords

  • Bone resorption
  • Electrophysiology
  • Motile activity
  • Prostanoid receptor agonists

ASJC Scopus subject areas

  • Physiology
  • Cell Biology

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