Dataset Information

TRPA1 Ion Channel Determines Beneficial and Detrimental Effects of GYY4137 in Murine Serum-Transfer Arthritis.

ABSTRACT: Modulation of nociception and inflammation by sulfide in rheumatoid arthritis and activation of transient receptor potential ankyrin 1 (TRPA1) ion channels by sulfide compounds are well documented. The present study aims to investigate TRPA1-mediated effects of sulfide donor GYY4137 in K/BxN serum-transfer arthritis, a rodent model of rheumatoid arthritis. TRPA1 and somatostatin sst4 receptor wild-type (WT) and knockout mice underwent K/BxN serum transfer and were treated daily with GYY4137. Functional and biochemical signs of inflammation were recorded, together with histological characterization. These included detection of hind paw mechanical hyperalgesia by dynamic plantar esthesiometry, hind paw volume by plethysmometry, and upside-down hanging time to failure. Hind paw erythema, edema, and passive movement range of tibiotarsal joints were scored. Somatostatin release from sensory nerve endings of TRPA1 wild-type and knockout mice in response to polysulfide was detected by radioimmunoassay. Polysulfide formation from GYY4137 was uncovered by cold cyanolysis. GYY4137 aggravated mechanical hyperalgesia in TRPA1 knockout mice but ameliorated it in wild-type ones. Arthritis score was lowered by GYY4137 in TRPA1 wild-type animals. Increased myeloperoxidase activity, plasma extravasation, and subcutaneous MIP-2 levels of hind paws were detected in TRPA1 knockout mice upon GYY4137 treatment. Genetic lack of sst4 receptors did not alter mechanical hyperalgesia, edema formation, hanging performance, arthritis score, plasma extravasation, or myeloperoxidase activity. TRPA1 WT animals exhibited smaller cartilage destruction upon GYY4137 administration. Sodium polysulfide caused TRPA1-dependent somatostatin release from murine nerve endings. Sulfide released from GYY4137 is readily converted into polysulfide by hypochlorite. Polysulfide potently activates human TRPA1 receptors expressed in Chinese hamster ovary (CHO) cells. According to our data, the protective effect of GYY4137 is mediated by TRPA1, while detrimental actions are independent of the ion channel in the K/BxN serum-transfer arthritis model in mice. At acidic pH in inflamed tissue sulfide is released from GYY4137 and reacts with neutrophil-derived hypochlorite. Resulting polysulfide might be responsible for TRPA1-mediated antinociceptive and anti-inflammatory as well as TRPA1-independent pro-inflammatory effects.

SUBMITTER: Batai IZ

PROVIDER: S-EPMC6737045 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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TRPA1 Ion Channel Determines Beneficial and Detrimental Effects of GYY4137 in Murine Serum-Transfer Arthritis.

Bátai István Z IZ Sár Cecília Pápainé CP Horváth Ádám Á Borbély Éva É Bölcskei Kata K Kemény Ágnes Á Sándor Zoltán Z Nemes Balázs B Helyes Zsuzsanna Z Perkecz Anikó A Mócsai Attila A Pozsgai Gábor G Pintér Erika E

Frontiers in pharmacology 20190904

Modulation of nociception and inflammation by sulfide in rheumatoid arthritis and activation of transient receptor potential ankyrin 1 (TRPA1) ion channels by sulfide compounds are well documented. The present study aims to investigate TRPA1-mediated effects of sulfide donor GYY4137 in K/BxN serum-transfer arthritis, a rodent model of rheumatoid arthritis. TRPA1 and somatostatin sst4 receptor wild-type (WT) and knockout mice underwent K/BxN serum transfer and were treated daily with GYY4137. Fun ...[more]

PMID: 31551776

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Project description:RationaleTransient receptor potential channels of the ankyrin subtype-1 (TRPA1) are non-selective cation channels that show high permeability to calcium. Previous studies from our laboratory have demonstrated that TRPA1 ion channels are expressed in adult mouse ventricular cardiomyocytes (CMs) and are localized at the z-disk, costamere and intercalated disk. The functional significance of TRPA1 ion channels in the modulation of CM contractile function have not been explored.ObjectiveTo identify the extent to which TRPA1 ion channels are involved in modulating CM contractile function and elucidate the cellular mechanism of action.Methods and resultsFreshly isolated CMs were obtained from murine heart and loaded with Fura-2 AM. Simultaneous measurement of intracellular free Ca2+ concentration ([Ca2+]i) and contractility was performed in individual CMs paced at 0.3 Hz. Our findings demonstrate that TRPA1 stimulation with AITC results in a dose-dependent increase in peak [Ca2+]i and a concomitant increase in CM fractional shortening. Further analysis revealed a dose-dependent acceleration in time to peak [Ca2+]i and velocity of shortening as well as an acceleration in [Ca2+]i decay and velocity of relengthening. These effects of TRPA1 stimulation were not observed in CMs pre-treated with the TRPA1 antagonist, HC-030031 (10 µmol/L) nor in CMs obtained from TRPA1-/- mice. Moreover, we observed no significant increase in cAMP levels or PKA activity in response to TRPA1 stimulation and the PKA inhibitor peptide (PKI 14-22; 100 nmol/L) failed to have any effect on the TRPA1-mediated increase in CM contractile function. However, TRPA1 stimulation resulted in a rapid phosphorylation of Ca2+/calmodulin-dependent kinase II (CaMKII) (1-5 min) that correlated with increases in CM [Ca2+]i and contractile function. Finally, all aspects of TRPA1-dependent increases in CM [Ca2+]i, contractile function and CaMKII phosphorylation were virtually abolished by the CaMKII inhibitors, KN-93 (10 µmol/L) and autocamtide-2-related peptide (AIP; 20 µmol/L).ConclusionsThese novel findings demonstrate that stimulation of TRPA1 ion channels in CMs results in activation of a CaMKII-dependent signaling pathway resulting in modulation of intracellular Ca2+ availability and handling leading to increases in CM contractile function. Cardiac TRPA1 ion channels may represent a novel therapeutic target for increasing the inotropic and lusitropic state of the heart.

Dataset Information

TRPA1 Ion Channel Determines Beneficial and Detrimental Effects of GYY4137 in Murine Serum-Transfer Arthritis.

Publications

TRPA1 Ion Channel Determines Beneficial and Detrimental Effects of GYY4137 in Murine Serum-Transfer Arthritis.

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