title: Functional role of the KCa3.1 potassium channel in synovial fibroblasts from rheumatoid arthritis patients.
abstract: Rheumatoid arthritis synovial fibroblasts (RA-SFs) show an aggressive phenotype and support joint inflammation and tissue destruction. New druggable targets in RA-SFs would therefore be of high therapeutic interest. The present study shows that the intermediate-conductance, calcium-activated potassium channel KCa3.1 (KCNN4) is expressed at the mRNA and protein level in RA-SFs, is functionally active, and has a regulatory impact on cell proliferation and secretion of pro-inflammatory and pro-destructive mediators. Whole-cell patch-clamp recordings identified KCa3.1 as the dominant potassium channel in the physiologically relevant membrane voltage range below 0 mV. Stimulation with transforming growth factor β1 (TGF-β1) significantly increased transcription, translation, and channel function of KCa3.1. Inhibition of KCa3.1 by the selective, pore-blocking inhibitor TRAM-34, (and, in part, by siRNA) significantly reduced cell proliferation, as well as expression and secretion of pro-inflammatory factors (IL-6, IL-8, and MCP1) and the tissue-destructive protease MMP3. These effects were observed in non-stimulated and/or TGF-β1-stimulated RA-SFs. Since small molecule-based interference with KCa3.1 is principally well tolerated in clinical settings, further evaluation of channel blockers in models of rheumatoid arthritis may be a promising approach to identify new pharmacological targets and develop new therapeutic strategies for this debilitating disease.
authors.affiliation: Center for Molecular Biomedicine, Department of Biophysics, Friedrich Schiller University of Jena and Jena University Hospital, Jena, Germany.
authors.forename: Kristin
authors.initials: K
authors.lastname: Friebel
authors.forename: Roland
authors.initials: R
authors.lastname: Schönherr
authors.forename: Raimund W
authors.initials: RW
authors.lastname: Kinne
authors.forename: Elke
authors.initials: E
authors.lastname: Kunisch
mesh_terms: D001172:Arthritis, Rheumatoid / Q000378:metabolism* / Q000473:pathology; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D005347:Fibroblasts / Q000502:physiology*; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels / Q000235:genetics / Q000378:metabolism*; D045726:Metalloproteases / Q000235:genetics / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013583:Synovial Membrane / Q000737:chemistry* / Q000166:cytology
chemical_list: D016207:Cytokines; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; C496923:KCNN4 protein, human; D011720:Pyrazoles; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C411671:TRAM 34; D045726:Metalloproteases