Inhibition of inwardly rectifying K+ current by external Ca2+ ions in freshly isolated rabbit osteoclasts.

Yamashita, Naohide; Ishii, Takayuki; Ogata, Etsuro; Matsumoto, Toshio

doi:10.1113/jphysiol.1994.sp020354

Cited by 14 publications

(14 citation statements)

References 33 publications

(42 reference statements)

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“…Extracellular Ca 2ϩ generates diverse biochemical and morphological changes (2,16,18,45). Extracellular Ca 2ϩ also modifies the electrophysiological profiles of osteoclasts; for instance it inhibits K ϩ channels (1,7,35,44) and activates Cl Ϫ channels (6,31,32,35). These Ca 2ϩ -sensing responses at the plasma membrane appear within 10 min after exposure to elevated extracellular Ca 2 levels.…”

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confidence: 96%

Phospholipase C-dependent Ca²⁺-sensing pathways leading to endocytosis and inhibition of the plasma membrane vacuolar H⁺-ATPase in osteoclasts

Sakai¹,

Moriura²,

Notomi³

et al. 2010

American Journal of Physiology-Cell Physiology

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In osteoclasts, elevation of extracellular Ca2+ is an endogenous signal that inhibits bone resorption. We recently found that an elevation of extracellular Ca2+ decreased proton extrusion through the plasma membrane vacuolar H+-ATPase (V-ATPase) rapidly. In this study we investigated mechanisms underlying this early Ca2+-sensing response, particularly in reference to the activity of the plasma membrane V-ATPase and to membrane retrieval. Whole cell clamp recordings allowed us to measure the V-ATPase currents and the cell capacitance (C(m)) simultaneously. C(m) is a measure of cell surface. Extracellular Ca2+ (2.5-40 mM) decreased C(m) and the V-ATPase current simultaneously. The decreased C(m), together with the enhanced uptake of a lipophilic dye (FM1-43), indicated that Ca2+ facilitated endocytosis. The endocytosis was blocked by dynamin inhibitors (dynasore and dynamin-inhibitory peptide), by small interfering RNA (siRNA) targeting for dynanmin-2 and also by bafilomycin A(1), a blocker of V-ATPases. The extracellular Ca2+-induced endocytosis and inhibition of the V-ATPase current were diminished by a phospholipase C inhibitor (U73122) and siRNA targeting for phospholipase C gamma2 subunit. Holding the cytosolic Ca2+ at either high (0.5-5 microM) or low levels or inhibiting calmodulin by an inhibitor (W7) or an antibody (anti-CaM) decreased the stimulated endocytosis and the inhibition of the V-ATPase current. These data suggest that extracellular Ca2+ facilitated dynamin- and V-ATPase-dependent endocytosis in association with an inhibition of the plasma membrane V-ATPase. Phospholipase C, cytosolic Ca2+, and calmodulin were involved in the signaling pathways. Membrane retrieval and the plasma membrane V-ATPase activity may cooperate during the early phase of Ca2+-sensing response in osteoclasts.

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confidence: 96%

Phospholipase C-dependent Ca²⁺-sensing pathways leading to endocytosis and inhibition of the plasma membrane vacuolar H⁺-ATPase in osteoclasts

Sakai¹,

Moriura²,

Notomi³

et al. 2010

American Journal of Physiology-Cell Physiology

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“…27, Weidema, A. F., Dixon, S. J. and Sims, S. M. Electrophysiological characterization of ion channels in osteoclasts isolated from human deciduous teeth, pages 5-11, copyright 2000, with permission from Elsevier Science. activity within minutes after breaking into the cell [25,33]. However, this observation is somewhat puzzling, because Kir2.1 channels are not considered to be regulated by G proteins in other systems.…”

Section: Regulationmentioning

confidence: 90%

“…Elevation of extracellular Ca 2+ appears to block the channel, reducing the conductance at all voltages [16,24,26]. It has also been suggested that binding of Ca 2+ to a cell surface receptor activates G proteins, which in turn inhibits the inward rectifier K + channel [25,28]. In this regard, the inward rectifier in osteoclasts has been shown to be regulated by G proteins, since inclusion of GTPγS or aluminum fluoride in the recording pipette inhibits channel Single-channel currents underlying the inward rectifier K + conductance have been recorded using the cell-attached patch configuration.…”

Section: Regulationmentioning

confidence: 96%

“…Indeed, high concentrations of extracellular divalent cations reduce the inward rectifier K + conductance in rat and rabbit osteoclasts [16,[24][25][26]. However, the basis of this effect is not resolved.…”

Section: Regulationmentioning

confidence: 97%

“…Patch-clamp recording is initiated by creating a seal between a blunt glass microelectrode and the membrane of the cell being studied, which allows membrane currents to be recorded. The types of K + channels that have been identified in osteoclasts are presented in Table I, and other cation and Cl -channels are summarized in Table II. rectifying K + currents [16,[20][21][22][23][24][25][26][27][28][29]. This current is readily identified under voltage clamp, based upon its characteristic voltage-activation properties and blockade by Ba 2+ and Cs + .…”

Section: Introductionmentioning

confidence: 99%

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Osteoclast Ion Channels Potential Targets for Antiresorptive Drugs.

Komarova¹,

Dixon²,

Sims³

2001

CPD

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This review summarizes the types of ion channels that have been identified in osteoclasts and considers their potential as targets for therapeutic agents aimed at the treatment of osteoporosis and other bone disorders. We focus on channels that have been identified using molecular and electrophysiological approaches. Numerous ion channels have been characterized, including K(+), H(+), Na(+), nonselective cation and Cl(-) channels. K(+) channels include an inward rectifier K(+) channel (Kir2.1) that is regulated by G proteins, and a transient outward rectifier K(+) channel (Kv1.3) that is regulated by cell-matrix interactions and by extracellular cations such as Ca(2+) and H(+). In addition, two classes of Ca(2+)-activated K(+) channels have been described--large and intermediate conductance channels, which are activated by increases of cytosolic Ca(2+) concentration. Other channels include stretch-activated nonselective cation channels and voltage-activated H(+) channels. A recent revelation is the presence of ligand-gated channels in osteoclasts, including P2X nucleotide receptors and glutamate-activated channels. Osteoclasts also exhibit an outwardly rectifying Cl(-) current that is activated by cell swelling. Kir2.1 and Cl(-) channels may be essential for resorptive activity because they provide pathways to compensate for charge accumulation arising from the electrogenic transport of H(+). As in other cell types, osteoclast ion channels also play important roles in setting the membrane potential, signal transduction and cell volume regulation. These channels represent potential targets for the development of antiresorptive drugs.

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Activation of Cl- channels by extracellular Ca2+ in freshly isolated rabbit osteoclasts

Fujita

Matsumoto

Kawashima³

et al. 1996

J. Cell. Physiol.

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Ionic channels regulated by extracellular Ca2+ concentration ([Ca2+]o) were examined in freshly isolated rabbit osteoclasts. K+ current was suppressed by intracellular and extracellular Cs+ ions. In this condition, high [Ca2+]o evoked an outwardly rectifying current with a reversal potential of about -25 mV. When the concentration of extracellular Cl ions was altered, the reversal potential of the outwardly rectifying current shifted as predicted by the Nernst equation. 4',4-diisothiocyanostilbene-2' 2-disulphonic acid (DIDS) inhibited the outwardly rectifying current. These results indicated that this current was carried through Cl- channels. Cd2+ or Ni2+ caused a transient activation of the Cl- current in contrast to the sustained activation elicited by Ca2+. Intracellular 20 mM ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA) inhibited the divalent cation-induced Cl- current. Either when the osmolarity of extracellular medium was increased, or when 100 microM cAMP was dissolved in the patch pipette solution, high [Ca2+]o still elicited the Cl- current, indicating that the divalent cation-induced Cl- current was carried through Ca(2+)-activated Cl- channels. Under perforated whole cell clamp extracellular divalent cations evoked the Cl- current, indicating that the activation of Cl- current did not arise from possible leakage of divalent cations from the extracellular medium under the whole cell clamp condition. This experiment further excluded a possible activation of volume-sensitive Cl- channels under whole cell clamp. Intracellular application of guanosine 5'-O-(3-thiotriphosphate) (GTP gamma S) activated the Cl current and it was inhibited by intracellular 20 mM EGTA, suggesting that the activation of Cl current was mediated through a G protein, and that an increase in [Ca2+]i was critical for the activation of Cl-channels. A protein phosphatase inhibitor, okadaic acid (100 nM), caused an irreversible activation of the Cl current, suggesting that protein phosphatase 1 or 2A was involved in the regulation of Ca(2+)-activated Cl- channels.

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Inhibition of inwardly rectifying K+ current by external Ca2+ ions in freshly isolated rabbit osteoclasts.

Cited by 14 publications

References 33 publications

Phospholipase C-dependent Ca²⁺-sensing pathways leading to endocytosis and inhibition of the plasma membrane vacuolar H⁺-ATPase in osteoclasts

Phospholipase C-dependent Ca²⁺-sensing pathways leading to endocytosis and inhibition of the plasma membrane vacuolar H⁺-ATPase in osteoclasts

Osteoclast Ion Channels Potential Targets for Antiresorptive Drugs.

Activation of Cl- channels by extracellular Ca2+ in freshly isolated rabbit osteoclasts

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Inhibition of inwardly rectifying K+ current by external Ca2+ ions in freshly isolated rabbit osteoclasts.

Cited by 14 publications

References 33 publications

Phospholipase C-dependent Ca2+-sensing pathways leading to endocytosis and inhibition of the plasma membrane vacuolar H+-ATPase in osteoclasts

Phospholipase C-dependent Ca2+-sensing pathways leading to endocytosis and inhibition of the plasma membrane vacuolar H+-ATPase in osteoclasts

Osteoclast Ion Channels Potential Targets for Antiresorptive Drugs.

Activation of Cl- channels by extracellular Ca2+ in freshly isolated rabbit osteoclasts

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Phospholipase C-dependent Ca²⁺-sensing pathways leading to endocytosis and inhibition of the plasma membrane vacuolar H⁺-ATPase in osteoclasts

Phospholipase C-dependent Ca²⁺-sensing pathways leading to endocytosis and inhibition of the plasma membrane vacuolar H⁺-ATPase in osteoclasts