Cellular channelopathy mediated by hypergravity: IL-6-mediated Nkcc1 activation and enhanced Trpm2 expression in rat atrium

Ji, Minjeong; Kim, Hyun Ji; Ahn, Chi Bum; Son, Kuk Hui; Hong, Jeong Hee

doi:10.1007/s00441-020-03299-2

Cited by 7 publications

(4 citation statements)

References 25 publications

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“…In addition, ischemic heart injury is mediated by the involvement of NKCC1 ( Ramasamy et al, 2001 ). IL-6 activates NKCC1 activity in cardiac tissue ( Ji et al, 2020 ) and induces NKCC1 phosphorylation and Cl – accumulation in sensory neurons ( Pieraut et al, 2011 ). The enrollment of NKCC1 is also associated with cellular volume change, membrane permeability, and subsequent change in water content in the brain ( Gong et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

“…Additionally, the multiple roles of IL-6 spread throughout both inflammatory and metabolic processes, making contributions to both of these vital pathways ( Jones and Jenkins, 2018 ). The signaling axis of IL-6 is considered the central process of inflammation and autoimmunity in various tissues including pulmonary, cardiac, and joints ( Hirano et al, 1987 ; Tanaka et al, 2014 ; Ji et al, 2020 ; Wang and He, 2020 ; Gong et al, 2021 ). IL-6 induces enhanced production of vascular endothelial growth factor, resulting in enhanced angiogenesis and vascular permeability ( Nakahara et al, 2003 ) and induced inflammatory signal of immune cells including T helper 17 (Th17) cells ( Swaak et al, 1988 ; Bettelli et al, 2006 ; Yue et al, 2010 ).…”

Section: Discussionmentioning

confidence: 99%

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Synovial Fluid of Patient With Rheumatoid Arthritis Enhanced Osmotic Sensitivity Through the Cytotoxic Edema Module in Synoviocytes

Ryu

Hong

2021

Front. Cell Dev. Biol.

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Rheumatoid arthritis (RA) is an autoimmune disease that causes inflammation of the synovial membrane ultimately leading to permanent damage in the affected joints. For this study, synovial fluids from 16 patients diagnosed with either RA or osteoarthritis (OA) were used to examine volume regulation and cooperative water channels, both of which are involved in the cytotoxic edema identified in RA-fibroblast-like synoviocytes (FLS). The osmolarity and inflammatory cytokine interleukin (IL)-6 of synovial fluids from RA patients were mildly enhanced compared to that from OA patients. RA-FLS demonstrated the enhanced property of regulatory volume increase in response to IL-6 and synovial fluids from RA patients. Although there was no difference in the protein expression of the volume-associated protein sodium–potassium–chloride cotransporter1 (NKCC1), its activity was increased by treatment with IL-6. Membrane localization of NKCC1 was also increased by IL-6 treatment. Additionally, both the protein and membrane expressions of aquaporin-1 were increased in RA-FLS by IL-6 stimulation. The IL-6-mediated enhanced osmotic sensitivity of RA-FLS likely involves NKCC1 and aquaporin-1, which mainly constitute the volume-associated ion transporter and water channel elements. These results suggest that RA-FLS provide enhanced electrolytes and concomitant water movement through NKCC1 and aquaporin-1, thereby inducing cellular swelling ultimately resulting in cytotoxic edema. Attenuation of cytotoxic edema and verification of its related mechanism will provide novel therapeutic approaches to RA treatment within the scope of cytotoxic edema.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Synovial Fluid of Patient With Rheumatoid Arthritis Enhanced Osmotic Sensitivity Through the Cytotoxic Edema Module in Synoviocytes

Ryu

Hong

2021

Front. Cell Dev. Biol.

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“…RA-FLSs attached to coverslips were loaded into the chamber with 6 µM BCECF-AM in the presence of 0.05% Pluronic F-127 for 15 min at room temperature. The dye-loaded RA-FLSs were perfused with a physiological salt solution (the composition is presented elsewhere [45]) for at least 5 min to stabilize the fluorescence before measuring pH i at 37 • C. The NBC activity of RA-FLSs was measured by incubating the cells with CO 2 -saturated HCO 3 − -buffered media with 5-(N-ethyl-N-isopropyl) amiloride (EIPA) (Sigma, Saint Louis, MO, USA) and the indicated reagents, including 100 ng/mL Dex (dexmedetomidine hydrochloride; Sigma, Saint Louis, MO, USA), 10 ng/mL TNF-α (R&D Systems, Minneapolis, MN, USA), 10 ng/mL EGF (Thermo Fisher, Waltham, MA, USA), and 50 ng/mL IL-6 (PeproTech, Cranbury, NJ, USA), followed by acidification with Na + -free HCO 3 − -buffered media. The emitted fluorescence of the dye-loaded cells was monitored using a CCD camera (Retiga 6000, Q-imaging, Tucson, AZ, USA) attached to an inverted microscope (Olympus, Tokyo, Japan) and analyzed using a MetaFluor system (Molecular Devices, San Jose, CA, USA).…”

Section: Measurement Of Cyclic Adenosine Monophosphate (Camp)mentioning

confidence: 99%

Multiple-Factors-Induced Rheumatoid Arthritis Synoviocyte Activation Is Attenuated by the α2-Adrenergic Receptor Agonist Dexmedetomidine

Lee

Hong

2023

IJMS

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Dexmedetomidine (Dex) has analgesic and sedative properties and anti-inflammatory functions. Although the effects of Dex on arthritis have been revealed, the physiological mechanism underlying the interaction between Dex and rheumatoid arthritis (RA)-mediated inflammatory cytokines has not been fully studied. Inflamed and migrated fibroblast-like synoviocytes (FLSs) are involved in RA severity. Thus, we aimed to determine the effects of Dex on RA-FLSs treated with inflammatory cytokines and a growth factor as multiple stimulating inputs. TNF-α, IL-6, and EGF as multiple stimulating inputs increased the cAMP concentration of RA-FLSs, while Dex treatment reduced cAMP concentration. Dex reduced electroneutral sodium-bicarbonate cotransporter 1 (NBCn1) expression, NBC activity, and subsequent RA-FLS migration. The mRNA expression levels of RA-related factors, such as inflammatory cytokines and osteoclastogenesis factors, were enhanced by multiple-input treatment. Notably, Dex effectively reduced these expression levels in RA-FLSs. These results indicate that multiple inflammatory or stimulating inputs enhance RA-FLS migration, and treatment with Dex relieves activated RA-FLSs, suggesting that Dex is a potential therapeutic drug for RA.

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“…As an important non-selective cation channel, transient receptor potential melastatin 2 (TRPM2), has an endogenous expression in many organs, such as brain ( Li and Jiao, 2020 ; Zong et al, 2022 ), heart ( Ji et al, 2021 ), liver ( Feng et al, 2019 ), kidney ( Wang et al, 2019 ), and lung ( Wang et al, 2020 ), and participates in various physiological and pathological processes. For example, TRPM2 channel is involved in temperature sensing ( Song et al, 2016 ; Kamm et al, 2021 ), synaptic plasticity regulation ( Wang et al, 2016 ), and insulin secretion ( Ito et al, 2017 ).…”

Section: Introductionmentioning

confidence: 99%

The identification of the key residues E829 and R845 involved in transient receptor potential melastatin 2 channel gating

Luo

Chen²,

Wu³

et al. 2022

Front. Aging Neurosci.

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Transient receptor potential melastatin 2 (TRPM2), a non-selective cation channel, is involved in many physiological and pathological processes, including temperature sensing, synaptic plasticity regulation, and neurodegenerative diseases. However, the gating mechanism of TRPM2 channel is complex, which hinders its functional research. With the discovery of the Ca2+ binding site in the S2–S3 domain of TRPM2 channel, more and more attention has been drawn to the role of the transmembrane segments in channel gating. In this study, we focused on the D820-F867 segment around the S2 domain, and identified the key residues on it. Functional assays of the deletion mutants displayed that the deletions of D820-W835 and L836-P851 destroyed channel function totally, indicating the importance of these two segments. Sequence alignments on them found three polar and charged residues with high conservation (D820, E829, and R845). D820A, E829A, and R845A which removed the charge and the side chain of the residues were tested by 500 μM adenosine diphosphate-ribose (ADPR) or 50 mM Ca2+. E829A and R845A affected the characteristic of channel currents, while D820A behaved similarly to WT, indicating the participations of E829 and R845 in channel gating. The charge reversing mutants, E829K and R845D were then constructed and the electrophysiological tests showed that E829A and E829K made the channel lose function. Interestingly, R845A and R845D exhibited an inactivation process when using 500 μM ADPR, but activated normally by 50 mM Ca2+. Our data suggested that the negative charge at E829 took a vital part in channel activation, and R845 increased the stability of the Ca2+ combination in S2-S3 domain, thus guaranteeing the opening of TRPM2 channel. In summary, our identification of the key residues E829 and R845 in the transmembrane segments of TRPM2. By exploring the gating process of TRPM2 channel, our work helps us better understand the mechanism of TRPM2 as a potential biomarker in neurodegenerative diseases, and provides a new approach for the prediction, diagnosis, and prognosis of neurodegenerative diseases.

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Cellular channelopathy mediated by hypergravity: IL-6-mediated Nkcc1 activation and enhanced Trpm2 expression in rat atrium

Cited by 7 publications

References 25 publications

Synovial Fluid of Patient With Rheumatoid Arthritis Enhanced Osmotic Sensitivity Through the Cytotoxic Edema Module in Synoviocytes

Synovial Fluid of Patient With Rheumatoid Arthritis Enhanced Osmotic Sensitivity Through the Cytotoxic Edema Module in Synoviocytes

Multiple-Factors-Induced Rheumatoid Arthritis Synoviocyte Activation Is Attenuated by the α2-Adrenergic Receptor Agonist Dexmedetomidine

The identification of the key residues E829 and R845 involved in transient receptor potential melastatin 2 channel gating

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