Contribution of Chloride Channel Conductance to the Regulation of Resting Membrane Potential in Chondrocytes

Funabashi, Kenji; Fujisawa, Masato; Yamamura, Hisao; Ohya, Susumu; Imaizumi, Yuji

doi:10.1254/jphs.10026sc

Cited by 29 publications

(34 citation statements)

References 13 publications

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“…Recently it has been reported that TMEM16A is expressed in rat articular chondrocytes (Ponce et al, 2012). TMEM16A has been suggested to be the molecular correlate for Ca 21 -activated Cl 2 channels in airway epithelial cells, vascular smooth muscle cells, and interstitial cells of Cajal in the gastrointestinal tract (Huang et al, 2012 ] i $ 1 mM (Funabashi et al, 2010a). However, the kinetics of the Cl 2 currents in this study differ substantially from these generated by TMEM16A channels (for example, the distinct tail currents).…”

Section: Discussionmentioning

confidence: 53%

“…In articular chondrocytes, voltage-dependent K 1 channels and two-pore domain K 1 channels contribute to the maintenance of the resting membrane potential (Wilson et al, 2004;Clark et al, 2011;Mobasheri et al, 2012). In addition, in human chondrocytes we have shown (Funabashi et al, 2010a) that blockage of Cl 2 channels causes a significant hyperpolarization that is followed by an enhanced Ca 21 influx through nonselective cation channels. In chondrocytes, an increase in intracellular Ca 21 concentration ([Ca 21 ] i ) facilitates the syntheses of aggrecan and type X collagen (Bonen and Schmid, 1991;Wu and Chen, 2000;Alford et al, 2003).…”

Section: Introductionmentioning

confidence: 76%

“…Our previous work showed that Cl 2 current(s) can contribute significantly to the regulation of resting membrane potential and modulate [Ca 21 ] i in the human chondrocyte cell line OUMS-27 (Funabashi et al, 2010a). However, the molecular component(s) and pathologic significance of Cl 2 current(s) in chondrocytes remained to be identified.…”

Section: Discussionmentioning

confidence: 99%

“…Previously, we reported that a Cl 2 conductance regulated the resting membrane potential in these OUMS-27 cells. However, the molecular identity and biophysical property were not identified in our initial study (Funabashi et al, 2010a). To obtain these data, the effect of siRNA knockdown of ClC-7 on the resting membrane potential in OUMS-27 cells was examined using whole-cell current-clamp recordings.…”

Section: Acid-sensitive CLmentioning

confidence: 99%

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The ClC-7 Chloride Channel Is Downregulated by Hypoosmotic Stress in Human Chondrocytes

et al. 2015

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Articular chondrocytes in osteoarthritis (OA) patients are exposed to hypoosmotic stress because the osmolality of this synovial fluid is significantly decreased. Hypoosmotic stress can cause an efflux of Cl 2 and an associated decrease of cell volume. We have previously reported that a Cl 2 conductance contributes to the regulation of resting membrane potential and thus can alter intracellular Ca 21 concentration ([Ca 21 ] i ) in human chondrocytes. The molecular identity and pathologic function of these Cl 2 channels, however, remained to be determined. Here, we show that the ClC-7 Cl 2 channel is strongly expressed in a human chondrocyte cell line (OUMS-27) and that it is responsible for Cl 2 currents that are activated by extracellular acidification (pH 5.0). These acid-sensitive currents are inhibited by 4,4ʹ-diisothiocyanatostilbene-2,2ʹ-disulfonic acid (DIDS; IC 50 5 13 mM) and are markedly reduced by small-interfering RNA-induced knockdown of ClC-7. DIDS hyperpolarized these chondrocytes, and this was followed by an increase in [Ca 21 ] i . ClC-7 knockdown caused a similar hyperpolarization of the membrane potential. Short-term culture (48 hours) in hypoosmotic medium (270 mOsm) reduced the expression of ClC-7 and decreased the acid-sensitive currents. Interestingly, these hypoosmotic culture conditions, or ClC-7 knockdown, resulted in enhanced cell death. Taken together, our results show that the significant hyperpolarization due to ClC-7 impairment in chondrocytes can significantly increase [Ca 21 ] i and cell death. Thus, downregulation of ClC-7 channels during the hypoosmotic stress that accompanies OA progression is one important concept of the complex etiology of OA. These findings suggest novel targets for therapeutic intervention(s) and drug development for OA.

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Section: Discussionmentioning

confidence: 53%

Section: Introductionmentioning

confidence: 76%

Section: Discussionmentioning

confidence: 99%

Section: Acid-sensitive CLmentioning

confidence: 99%

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The ClC-7 Chloride Channel Is Downregulated by Hypoosmotic Stress in Human Chondrocytes

et al. 2015

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“…30) Cell isolation from normal rat prostate and implanted UGS was performed as previously reported. 31) Prior to the fluorescence measurements with DiBAC 4 (3), isolated cells were preincubated in normal N-(2-hydroxyethyl)piperazine-N′-2-ethanesulfonic acid (HEPES) buffer (in mM, 137 NaCl, 5.9 KCl, 2.2 CaCl 2 , 1.2 MgCl 2 , 10 glucose, and 10 HEPES, pH 7.4) containing 100 nM DiBAC 4 (3) for 30 min at room temperature.…”

Section: +mentioning

confidence: 99%

Down-Regulation of the Large-Conductance Ca2+-Activated K+ Channel, KCa1.1 in the Prostatic Stromal Cells of Benign Prostate Hyperplasia

Niwa

Ohya

Kojima

et al. 2012

Biological & Pharmaceutical Bulletin

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The role of the membrane potential in chondrocyte volume regulation

Lewis

Asplin

Bruce

et al. 2011

Journal Cellular Physiology

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Many cell types have significant negative resting membrane potentials (RMPs) resulting from the activity of potassium-selective and chloride-selective ion channels. In excitable cells, such as neurones, rapid changes in membrane permeability underlie the generation of action potentials. Chondrocytes have less negative RMPs and the role of the RMP is not clear. Here we examine the basis of the chondrocyte RMP and possible physiological benefits. We demonstrate that maintenance of the chondrocyte RMP involves gadolinium-sensitive cation channels. Pharmacological inhibition of these channels causes the RMP to become more negative (100 µM gadolinium: ΔVm = −30 ± 4 mV). Analysis of the gadolinium-sensitive conductance reveals a high permeability to calcium ions (PCa/PNa ≈80) with little selectivity between monovalent ions; similar to that reported elsewhere for TRPV5. Detection of TRPV5 by PCR and immunohistochemistry and the sensitivity of the RMP to the TRPV5 inhibitor econazole (ΔVm = −18 ± 3 mV) suggests that the RMP may be, in part, controlled by TRPV5. We investigated the physiological advantage of the relatively positive RMP using a mathematical model in which membrane stretch activates potassium channels allowing potassium efflux to oppose osmotic water uptake. At very negative RMP potassium efflux is negligible, but at more positive RMP it is sufficient to limit volume increase. In support of our model, cells clamped at −80 mV and challenged with a reduced osmotic potential swelled approximately twice as much as cells at +10 mV. The positive RMP may be a protective adaptation that allows chondrocytes to respond to the dramatic osmotic changes, with minimal changes in cell volume. J. Cell. Physiol. 226: 2979–2986, 2011. © 2011 Wiley-Liss, Inc.

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Contribution of Chloride Channel Conductance to the Regulation of Resting Membrane Potential in Chondrocytes

Cited by 29 publications

References 13 publications

The ClC-7 Chloride Channel Is Downregulated by Hypoosmotic Stress in Human Chondrocytes

The ClC-7 Chloride Channel Is Downregulated by Hypoosmotic Stress in Human Chondrocytes

Down-Regulation of the Large-Conductance Ca<sup>2+</sup>-Activated K<sup>+</sup> Channel, K<sub>Ca</sub>1.1 in the Prostatic Stromal Cells of Benign Prostate Hyperplasia

The role of the membrane potential in chondrocyte volume regulation

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