Targeting KCa1.1 Channels with a Scorpion Venom Peptide for the Therapy of Rat Models of Rheumatoid Arthritis

Tanner, Mark R.; Pennington, Michael W.; Chamberlain, Brayden H.; Huq, Redwan; Gehrmann, Elizabeth J.; Laragione, Teresina; Gulko, Pércío S.; Beeton, Christine

doi:10.1124/jpet.117.245118

Cited by 22 publications

(20 citation statements)

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“…Furthermore, KCa1.1 blockers reduce disease severity in animal models of RA [17, 21]. However, similar to what is observed in animal models of autoimmunity treated with Kv1.3 blockers, rats with a model of RA treated with a KCa1.1 blocker still exhibit signs of disease, but at lower levels than vehicle-treated animals [17, 21].…”

Section: Introductionmentioning

confidence: 88%

“…The KCa1.1 blocker paxilline was purchased from Fermentek (Jerusalem, Israel), and the Kv1.3 blocker ShK-186/Dalazatide, synthesized under good manufacturing practice conditions by CSBio (Menlo Park, CA, USA), was a kind gift from Kineta, Inc. (Seattle, WA, USA). The KCa1.1 blocker IbTX was synthesized as described previously [21]. Each batch of blockers was tested for channel block by patch-clamping on HEK 293 cells stably expressing KCa1.1 and on L929 cells stably expressing Kv1.3 [38] using a Port-a-Patch automated patch-clamp system (Nanion, Munich, Germany) as described elsewhere [11, 21].…”

Section: Methodsmentioning

confidence: 99%

“…We have previously demonstrated that FLS from patients with RA and from animal models of RA upregulate the potassium channel KCa1.1 at their plasma membrane [16–20]. KCa1.1 blockade with selective inhibitors, such as the fungal alkaloid paxilline and the Buthus tamulus scorpion venom toxin iberiotoxin (IbTX), reduces FLS invasion and cytokine and chemokine secretion ex vivo [17, 19, 21]. Furthermore, KCa1.1 blockers reduce disease severity in animal models of RA [17, 21].…”

Section: Introductionmentioning

confidence: 99%

“…KCa1.1 blockade with selective inhibitors, such as the fungal alkaloid paxilline and the Buthus tamulus scorpion venom toxin iberiotoxin (IbTX), reduces FLS invasion and cytokine and chemokine secretion ex vivo [17, 19, 21]. Furthermore, KCa1.1 blockers reduce disease severity in animal models of RA [17, 21]. However, similar to what is observed in animal models of autoimmunity treated with Kv1.3 blockers, rats with a model of RA treated with a KCa1.1 blocker still exhibit signs of disease, but at lower levels than vehicle-treated animals [17, 21].…”

Section: Introductionmentioning

confidence: 99%

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KCa1.1 and Kv1.3 channels regulate the interactions between fibroblast-like synoviocytes and T lymphocytes during rheumatoid arthritis

et al. 2019

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BackgroundFibroblast-like synoviocytes (FLS) and CCR7− effector memory T (TEM) cells are two of the major cell types implicated in the progression of rheumatoid arthritis (RA). In particular, FLS become highly invasive, whereas TEM cells proliferate and secrete proinflammatory cytokines, during RA. FLS and T cells may also interact and influence each other’s phenotypes. Inhibition of the pathogenic phenotypes of both FLS and TEM cells can be accomplished by selectively blocking the predominant potassium channels that they upregulate during RA: KCa1.1 (BK, Slo1, MaxiK, KCNMA1) upregulated by FLS and Kv1.3 (KCNA3) upregulated by activated TEM cells. In this study, we investigated the roles of KCa1.1 and Kv1.3 in regulating the interactions between FLS and TEM cells and determined if combination therapies of KCa1.1- and Kv1.3-selective blockers are more efficacious than monotherapies in ameliorating disease in rat models of RA.MethodsWe used in vitro functional assays to assess the effects of selective KCa1.1 and Kv1.3 channel inhibitors on the interactions of FLS isolated from rats with collagen-induced arthritis (CIA) with syngeneic TEM cells. We also used flow cytometric analyses to determine the effects of KCa1.1 blockers on the expression of proteins used for antigen presentation on CIA-FLS. Finally, we used the CIA and pristane-induced arthritis models to determine the efficacy of combinatorial therapies of KCa1.1 and Kv1.3 blockers in reducing disease severity compared with monotherapies.ResultsWe show that the interactions of FLS from rats with CIA and of rat TEM cells are regulated by KCa1.1 and Kv1.3. Inhibiting KCa1.1 on FLS reduces the ability of FLS to stimulate TEM cell proliferation and migration, and inhibiting Kv1.3 on TEM cells reduces TEM cells’ ability to enhance FLS expression of KCa1.1 and major histocompatibility complex class II protein, as well as stimulates their invasion. Furthermore, we show that combination therapies of selective KCa1.1 and Kv1.3 blockers are more efficacious than monotherapies at reducing signs of disease in two rat models of RA.ConclusionsOur results demonstrate the importance of KCa1.1 and Kv1.3 in regulating FLS and TEM cells during RA, as well as the value of combined therapies targeting both of these cell types to treat RA.Electronic supplementary materialThe online version of this article (10.1186/s13075-018-1783-9) contains supplementary material, which is available to authorized users.

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Section: Introductionmentioning

confidence: 88%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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KCa1.1 and Kv1.3 channels regulate the interactions between fibroblast-like synoviocytes and T lymphocytes during rheumatoid arthritis

et al. 2019

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“…They were euthanized 24 h later for collection of the hind limbs, fixation in 10% buffered formalin, paraffin embedding, and sectioning. Sections were stained for the detection of PEG-HCCs and podoplanin as described [ 16 , 33 ]. Briefly, sections were dewaxed in xylenes, rehydrated through an ethanol gradient, and non-specific binding sites were blocked overnight with PBS + 5% goat serum + 5% bovine serum albumin.…”

Section: Methodsmentioning

confidence: 99%

Antioxidant Carbon Nanoparticles Inhibit Fibroblast-Like Synoviocyte Invasiveness and Reduce Disease Severity in a Rat Model of Rheumatoid Arthritis

et al. 2020

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Reactive oxygen species have been involved in the pathogenesis of rheumatoid arthritis (RA). Our goal was to determine the effects of selectively scavenging superoxide (O2•−) and hydroxyl radicals with antioxidant nanoparticles, called poly(ethylene glycol)-functionalized hydrophilic carbon clusters (PEG-HCCs), on the pathogenic functions of fibroblast-like synoviocytes (FLS) from patients with rheumatoid arthritis (RA) and on the progression of an animal model of RA. We used human FLS from patients with RA to determine PEG-HCC internalization and effects on FLS cytotoxicity, invasiveness, proliferation, and production of proteases. We used the pristane-induced arthritis (PIA) rat model of RA to assess the benefits of PEG-HCCs on reducing disease severity. PEG-HCCs were internalized by RA-FLS, reduced their intracellular O2•−, and reduced multiple measures of their pathogenicity in vitro, including proliferation and invasion. In PIA, PEG-HCCs caused a 65% reduction in disease severity, as measured by a standardized scoring system of paw inflammation and caused a significant reduction in bone and tissue damage, and circulating rheumatoid factor. PEG-HCCs did not induce lymphopenia during PIA. Our study demonstrated a role for O2•− and hydroxyl radicals in the pathogenesis of a rat model of RA and showed efficacy of PEG-HCCs in treating a rat model of RA.

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New potential therapeutic approaches targeting synovial fibroblasts in rheumatoid arthritis

Alcaraz

2021

Biochemical Pharmacology

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Targeting KCa1.1 Channels with a Scorpion Venom Peptide for the Therapy of Rat Models of Rheumatoid Arthritis

Cited by 22 publications

References 51 publications

KCa1.1 and Kv1.3 channels regulate the interactions between fibroblast-like synoviocytes and T lymphocytes during rheumatoid arthritis

KCa1.1 and Kv1.3 channels regulate the interactions between fibroblast-like synoviocytes and T lymphocytes during rheumatoid arthritis

Antioxidant Carbon Nanoparticles Inhibit Fibroblast-Like Synoviocyte Invasiveness and Reduce Disease Severity in a Rat Model of Rheumatoid Arthritis

New potential therapeutic approaches targeting synovial fibroblasts in rheumatoid arthritis

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