An environmental sensor, TRPV4 is a novel regulator of intracellular Ca<sup>2+</sup> in human synoviocytes

Itoh, Yoshio; Hatano, Noriyuki; Hayashi, Hidetoshi; Onozaki, Kikuo; Miyazawa, Keiji; Muraki, Katsuhiko

doi:10.1152/ajpcell.00204.2009

Cited by 40 publications

(50 citation statements)

References 26 publications

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“…33 The down regulation of TRPV4 in OA cells may be an indication that these cells do not produce as much SOX9 as normal cells, inhibiting differentiation into chondrocytes and further progressing the disease state. Because TRPV4 is a calcium ion channel that is known to be sensitive to osmotic changes in the joint, 34 we looked at the effect of changes of culture medium osmolality. Intracellular calcium levels appeared to change with the osmolality of the culture medium in OA cells concurrently with TRPV4 levels.…”

Section: Discussionmentioning

confidence: 99%

Ion channel expression and function in normal and osteoarthritic human synovial fluid progenitor cells

et al. 2016

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Osteoarthritis (OA) is a chronic disease affecting the cartilage of over 15% of Canadians. Synovial fluid mesenchymal progenitor cells (sfMPCs) are present in joints and are thought to contribute to healing. OA sfMPCs have a greater proliferative ability but decreased chondrogenic potential. However, little is known about the factors influencing/regulating the differences between normal and OA sfMPCs. Recently, our lab has shown that sfMPC chondrogenic differentiation in vitro is favorably biased toward a similar osmotic environment as they experience in vivo. The current study now examines the expression and functionality of a variety of ion channels in sfMPCs derived from normal individuals and early OA patients. Results indicated that there is differential ion channel regulation at the functional level and expression level in early OA sfMPCs. All ion channels were upregulated in early OA compared to normal sfMPCs with the exception of KCNMA1 at the mRNA level. At the protein level, TRPV4 was over expressed in early OA sfMPCs, while KCNJ12 and KCNMA1 were unchanged between normal and early OA sfMPCs. At the functional level, the inward rectifying potassium channel was under expressed in early OA sfMPCs, however the membrane potential was unchanged between normal and early OA sfMPCs. In the synovial environment itself, a number of differences in ion concentration between normal and early OA synovial fluid were observed. These findings suggest that normal and OA progenitor cells demonstrate functional differences in how they interact with the synovial ion environment.

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Section: Discussionmentioning

confidence: 99%

Ion channel expression and function in normal and osteoarthritic human synovial fluid progenitor cells

et al. 2016

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“…Patch-clamp experiments were performed as described previously (16 Measurement of the Ca 2ϩ fluorescence ratio. HEK cells and human synoviocytes were loaded with 10 M fura 2-AM in the HEPES solution for 30 min at room temperature.…”

Section: Methodsmentioning

confidence: 99%

The NADPH oxidase inhibitor diphenyleneiodonium activates the human TRPA1 nociceptor

Suzuki

Hatano

Muraki

et al. 2014

American Journal of Physiology-Cell Physiology

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Transient receptor potential ankyrin 1 (TRPA1) is a Ca 2ϩ -permeable nonselective cation channel expressed in neuronal and nonneuronal cells and plays an important role in acute and inflammatory pain. Here, we show that an NADPH oxidase (NOX) inhibitor, diphenyleneiodonium (DPI), functions as a TRPA1 activator in human embryonic kidney cells expressing human TRPA1 (HEK-TRPA1) and in human fibroblast-like synoviocytes. Application of DPI at 0.03-10 M induced a Ca 2ϩ response in HEK-TRPA1 cells in a concentration-dependent manner. The Ca 2ϩ response was effectively blocked by a selective TRPA1 antagonist, HC-030031 (HC). In contrast, DPI had no effect on HEK cells expressing TRPV1-V4 or TRPM8. Four other NOX inhibitors, apocynin (APO), VAS2870 (VAS), plumbagin, and 2-acetylphenothiazine, also induced a Ca 2ϩ response in HEK-TRPA1 cells, which was inhibited by pretreatment with HC. In the presence of 5 mM glutathione, the Ca 2ϩ response to DPI was effectively reduced. Moreover, mutation of cysteine 621 in TRPA1 substantially inhibited the DPIinduced Ca 2ϩ response, while it did not inhibit the APO-and VASinduced responses. The channel activity was induced by DPI in excised membrane patches with both outside-out and inside-out configurations. Internal application of neomycin significantly inhibited the DPI-induced inward currents. In inflammatory synoviocytes with TRPA1, DPI evoked a Ca 2ϩ response that was sensitive to HC. In mice, intraplantar injection of DPI caused a pain-related response which was inhibited by preadministration with HC. Taken together, our findings demonstrate that DPI and other NOX inhibitors activate human TRPA1 without mediating NOX. calcium channel; transient receptor potential; NADPH oxidase inhibitors TRANSIENT RECEPTOR POTENTIAL ANKYRIN 1 (TRPA1), a Ca 2ϩ -permeable nonselective cation channel widely expressed in neuronal and nonneuronal cells, is activated by noxious cold, mechanical stimulation, irritant chemicals, and some clinical drugs (1,7,12,17,26,28,30,36). Because transgenic mice lacking TRPA1 have suppressed sensitivity to mechanical stimulation, cold stimuli, and TNF␣-induced mechanical hyperalgesia (5,8,20,23,33), the channel has been proposed to be a nociceptor mediating acute and inflammatory pain (3,23,33). Mutagenesis studies have revealed that the cysteine residues 414, 421, and 621 of human TRPA1 are targeted by physiological and nonphysiological electrophilic compounds that activate the channel (14, 26). In contrast, nonelectrophilic compounds, such as ⌬9-tetrahydrocannabinol, nicotine, and menthol, activate TRPA1 via unknown mechanisms (17,18,38). Because numerous structurally unrelated compounds stimulate TRPA1, greater attention should be given to whether common clinical drugs and experimental pharmacological agents activate the channel.The NADPH oxidases (NOXs), a family of transmembrane proteins comprising seven members (NOX1-NOX5, DUOX1, and DUOX2), function as transmembrane electron transporters that use cytosolic NADPH as electron donor and oxygen as electron a...

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“…Whole cell patch-clamp experiments were performed as described previously (18). The resistance of electrodes was 3-5 M⍀ when filled with the pipette solution [in mM: 110 Cs-aspartate, 30 CsCl, 1 MgCl2, 10 HEPES, 1 EGTA, 2 Na 2ATP (pH 7.2 by CsOH)].…”

Section: Methodsmentioning

confidence: 99%

Stimulation of human TRPA1 channels by clinical concentrations of the antirheumatic drug auranofin

Hatano

Suzuki

Muraki

et al. 2013

American Journal of Physiology-Cell Physiology

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Gold compounds, which were widely used to treat rheumatoid arthritis, have been recently used as experimental agents for tumor treatment. Transient receptor potential (TRP) ankyrin repeat 1 (TRPA1) is a Ca(2+)-permeable ion channel that senses acute and inflammatory pain signals. Electrophilic compounds such as mustard oil and cinnamaldehyde activate TRPA1 by interacting with TRPA1 cysteine residues. Here we investigate the effects of the gold compound auranofin (AUR) on TRPA1 channels. Intracellular Ca(2+) and whole cell patch-clamp recordings were performed on human embryonic kidney cells transiently expressed with TRPA1, TRP melastatin 8 (TRPM8), and vanilloid type TRP (TRPV1-4) channels. AUR stimulated TRPA1 in a concentration-dependent manner with a half-maximum potency of around 1.0 μM. The AUR-induced response was effectively blocked by HC030031, a TRPA1 antagonist. On the other hand, AUR failed to activate TRPM8 and TRPV1-4 channels, which are highly expressed in sensory neurons as nociceptors. The stimulatory effect on TRPA1 channels depended on the C414, C421, C621, and C633 cysteine residues and not on the inhibition of thioredoxin reductase by AUR. Moreover, AUR effectively activated TRPA1 channels expressed in human differentiated neuroblastoma cell lines. The study shows that AUR is a potent stimulator of TRPA1 channels.

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An environmental sensor, TRPV4 is a novel regulator of intracellular Ca²⁺ in human synoviocytes

Cited by 40 publications

References 26 publications

Ion channel expression and function in normal and osteoarthritic human synovial fluid progenitor cells

Ion channel expression and function in normal and osteoarthritic human synovial fluid progenitor cells

The NADPH oxidase inhibitor diphenyleneiodonium activates the human TRPA1 nociceptor

Stimulation of human TRPA1 channels by clinical concentrations of the antirheumatic drug auranofin

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An environmental sensor, TRPV4 is a novel regulator of intracellular Ca2+ in human synoviocytes

Cited by 40 publications

References 26 publications

Ion channel expression and function in normal and osteoarthritic human synovial fluid progenitor cells

Ion channel expression and function in normal and osteoarthritic human synovial fluid progenitor cells

The NADPH oxidase inhibitor diphenyleneiodonium activates the human TRPA1 nociceptor

Stimulation of human TRPA1 channels by clinical concentrations of the antirheumatic drug auranofin

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An environmental sensor, TRPV4 is a novel regulator of intracellular Ca²⁺ in human synoviocytes