Premium
Functional role of the KCa3.1 potassium channel in synovial fibroblasts from rheumatoid arthritis patients
Author(s) -
Friebel Kristin,
Schönherr Roland,
Kinne Raimund W.,
Kunisch Elke
Publication year - 2015
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.24924
Subject(s) - potassium channel , rheumatoid arthritis , inflammation , secretion , arthritis , synovial membrane , cell , cell growth , medicine , voltage gated potassium channel , microbiology and biotechnology , cancer research , chemistry , pharmacology , biology , biochemistry
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. J. Cell. Physiol. 230: 1677–1688, 2015. © 2014 Wiley Periodicals, Inc., A Wiley Company