KCa 3.1 in inflammatory bowel disease

D. Strøbæk, D. T. Brown, D. P. Jenkins, Yi-Je Chen, N. Coleman, Y. Ando, P. Chiu, S. Jørgensen, J. Demnitz, Heike Wulff, Palle Christophersen

Research output: Contribution to journalArticle

43 Citations (Scopus)

Abstract

Background and Purpose The KCa3.1 channel is a potential target for therapy of immune disease. We identified a compound from a new chemical class of KCa3.1 inhibitors and assessed in vitro and in vivo inhibition of immune responses. Experimental Approach We characterized the benzothiazinone NS6180 (4-[[3-(trifluoromethyl)phenyl]methyl]-2H-1,4- benzothiazin-3(4H)-one) with respect to potency and molecular site of action on KCa3.1 channels, selectivity towards other targets, effects on T-cell activation as well as pharmacokinetics and inflammation control in colitis induced by 2,4-dinitrobenzene sulfonic acid, a rat model of inflammatory bowel disease (IBD). Key Results NS6180 inhibited cloned human KCa3.1 channels (IC50 = 9 nM) via T250 and V275, the same amino acid residues conferring sensitivity to triarylmethanes such as like TRAM-34. NS6180 inhibited endogenously expressed KCa3.1 channels in human, mouse and rat erythrocytes, with similar potencies (15-20 nM). NS6180 suppressed rat and mouse splenocyte proliferation at submicrolar concentrations and potently inhibited IL-2 and IFN-γ production, while exerting smaller effects on IL-4 and TNF-α and no effect on IL-17 production. Antibody staining showed KCa3.1 channels in healthy colon and strong up-regulation in association with infiltrating immune cells after induction of colitis. Despite poor plasma exposure, NS6180 (3 and 10 mg·kg-1 b.i.d.) dampened colon inflammation and improved body weight gain as effectively as the standard IBD drug sulfasalazine (300 mg·kg-1 q.d.). Conclusions and Implications NS6180 represents a novel class of K Ca3.1 channel inhibitors which inhibited experimental colitis, suggesting KCa3.1 channels as targets for pharmacological control of intestinal inflammation.

Original languageEnglish (US)
Pages (from-to)432-444
Number of pages13
JournalBritish Journal of Pharmacology
Volume168
Issue number2
DOIs
StatePublished - Jan 2013

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Inflammatory Bowel Diseases
Colitis
Inflammation
Colon
Sulfasalazine
Sulfonic Acids
Interleukin-17
Immune System Diseases
4-((3-(trifluoromethyl)phenyl)methyl)-2H-1,4-benzothiazin-3(4H)-one
Interleukin-4
Inhibitory Concentration 50
Weight Gain
Interleukin-2
Up-Regulation
Pharmacokinetics
Erythrocytes
Body Weight
Pharmacology
Staining and Labeling
T-Lymphocytes

Keywords

  • autoimmune disease
  • DNBS-induced colitis
  • Gárdos channel
  • IBD
  • IK channel
  • K 3.1
  • KCNN4
  • NS6180
  • T-cell activation
  • TRAM-34

ASJC Scopus subject areas

  • Pharmacology

Cite this

Strøbæk, D., Brown, D. T., Jenkins, D. P., Chen, Y-J., Coleman, N., Ando, Y., ... Christophersen, P. (2013). KCa 3.1 in inflammatory bowel disease. British Journal of Pharmacology, 168(2), 432-444. https://doi.org/10.1111/j.1476-5381.2012.02143.x

KCa 3.1 in inflammatory bowel disease. / Strøbæk, D.; Brown, D. T.; Jenkins, D. P.; Chen, Yi-Je; Coleman, N.; Ando, Y.; Chiu, P.; Jørgensen, S.; Demnitz, J.; Wulff, Heike; Christophersen, Palle.

In: British Journal of Pharmacology, Vol. 168, No. 2, 01.2013, p. 432-444.

Research output: Contribution to journalArticle

Strøbæk, D, Brown, DT, Jenkins, DP, Chen, Y-J, Coleman, N, Ando, Y, Chiu, P, Jørgensen, S, Demnitz, J, Wulff, H & Christophersen, P 2013, 'KCa 3.1 in inflammatory bowel disease', British Journal of Pharmacology, vol. 168, no. 2, pp. 432-444. https://doi.org/10.1111/j.1476-5381.2012.02143.x
Strøbæk D, Brown DT, Jenkins DP, Chen Y-J, Coleman N, Ando Y et al. KCa 3.1 in inflammatory bowel disease. British Journal of Pharmacology. 2013 Jan;168(2):432-444. https://doi.org/10.1111/j.1476-5381.2012.02143.x
Strøbæk, D. ; Brown, D. T. ; Jenkins, D. P. ; Chen, Yi-Je ; Coleman, N. ; Ando, Y. ; Chiu, P. ; Jørgensen, S. ; Demnitz, J. ; Wulff, Heike ; Christophersen, Palle. / KCa 3.1 in inflammatory bowel disease. In: British Journal of Pharmacology. 2013 ; Vol. 168, No. 2. pp. 432-444.
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