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Research ArticleDrug Discovery and Translational Medicine

Targeting KCa1.1 channels with a scorpion venom peptide for the therapy of rat models of rheumatoid arthritis

Mark R. Tanner, Michael W. Pennington, Brayden H. Chamberlain, Redwan Huq, Elizabeth J. Gehrmann, Teresina Laragione, Percio S. Gulko and Christine Beeton
Journal of Pharmacology and Experimental Therapeutics February 16, 2018, jpet.117.245118; DOI: https://doi.org/10.1124/jpet.117.245118
Mark R. Tanner
1 Baylor College of Medicine;
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Michael W. Pennington
2 Peptides International;
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Brayden H. Chamberlain
1 Baylor College of Medicine;
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Redwan Huq
1 Baylor College of Medicine;
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Elizabeth J. Gehrmann
1 Baylor College of Medicine;
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Teresina Laragione
3 Icahn School of Medicine at Mount Sinai
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Percio S. Gulko
3 Icahn School of Medicine at Mount Sinai
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Christine Beeton
1 Baylor College of Medicine;
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Abstract

Fibroblast-like synoviocytes (FLS) are a key cell-type involved in rheumatoid arthritis (RA) progression. We previously identified the KCa1.1 potassium channel (Maxi-K, BK, Slo 1, KCNMA1) as a regulator of FLS and that KCa1.1 inhibition reduces disease severity in RA animal models. However, systemic KCa1.1 block causes multiple side effects and in this study, we aimed to determine whether the KCa1.1 β1-3-specific venom peptide blocker iberiotoxin (IbTX) reduces disease severity in animal models of RA without inducing major side effects. We used immunohistochemistry to identify IbTX-sensitive KCa1.1 subunits in joints of rats with a model of RA. Patch clamp and functional assays were used to determine if IbTX can regulate FLS through targeting KCa1.1. We then tested the efficacy of IbTX in ameliorating disease in two rat models of RA. Finally, we determined if IbTX causes side-effects including incontinence or tremors in rats, compared to those treated with the small molecule KCa1.1 blocker paxilline. IbTX-sensitive subunits of KCa1.1 are expressed by FLS in joints of rats with experimental arthritis. IbTX inhibits KCa1.1 channels expressed by FLS from patients with RA and by FLS from rat models of RA and reduces FLS invasiveness. IbTX significantly reduces disease severity in two rat models of RA. Unlike paxilline, IbTX does not induce tremors or incontinence in rats. Overall, IbTX inhibits KCa1.1 channels on FLS and treats rat models of RA without inducing side effects associated with non-specific KCa1.1 blockade and could become the basis for the development of a new treatment for RA.

  • calcium-activated potassium channels
  • drug development
  • potassium channels
  • rheumatoid arthritis
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 384 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 384, Issue 2
1 Feb 2023
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Research ArticleDrug Discovery and Translational Medicine

Targeting KCa1.1 channels with a scorpion venom peptide for the therapy of rat models of rheumatoid arthritis

Mark R. Tanner, Michael W. Pennington, Brayden H. Chamberlain, Redwan Huq, Elizabeth J. Gehrmann, Teresina Laragione, Percio S. Gulko and Christine Beeton
Journal of Pharmacology and Experimental Therapeutics February 16, 2018, jpet.117.245118; DOI: https://doi.org/10.1124/jpet.117.245118

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Research ArticleDrug Discovery and Translational Medicine

Targeting KCa1.1 channels with a scorpion venom peptide for the therapy of rat models of rheumatoid arthritis

Mark R. Tanner, Michael W. Pennington, Brayden H. Chamberlain, Redwan Huq, Elizabeth J. Gehrmann, Teresina Laragione, Percio S. Gulko and Christine Beeton
Journal of Pharmacology and Experimental Therapeutics February 16, 2018, jpet.117.245118; DOI: https://doi.org/10.1124/jpet.117.245118
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