Selective targeting of KCa1.1 αβ3 channels reduces invasiveness of RA synovial fibroblasts, suggesting a promising therapeutic approach for rheumatoid arthritis.
Selective blockade of the KCa1.1 αβ3 channel represents a potential targeted therapy to inhibit pathogenic synovial fibroblasts in rheumatoid arthritis.
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Fibroblast-like synoviocytes (FLS) play major roles in the pathogenesis of rheumatoid arthritis (RA). Human and rat FLS express the KCa1.1 channel (BK, Maxi-K, Slo1, and KCNMA1) as their major potassium channel at the plasma membrane. Reducing the expression or function of this channel inhibits pathogenic functions of FLS in vitro and stops disease progression in rat models of RA. However, KCa1.1 is ubiquitously expressed, leading to severe side effects. KCa1.1, however, remains a viable therapeutic target as its α subunits can be co-expressed with β and γ regulatory subunits, which alter the biophysical and pharmacological fingerprints of the channel and have a restricted tissue distribution. Highly invasive RA-FLS preferentially express KCa1.1 αβ3, whereas less invasive FLS express KCa1.1 αβ1. The knockdown of β3, but not β1, reduces the invasive capacity of RA-FLS. Development of a selective blocker of KCa1.1 αβ3 might be of interest as a potential FLS-targeted therapeutic for RA. • Synovial fibroblasts play a central role in the pathogenesis of RA. • KCa1.1 is the major potassium channel at the surface of synovial fibroblasts. • Switch from KCa1.1 αβ1 to αβ3 during RA. • KCa1.1 αβ3 as an attractive target for the therapy of RA.
Elston et al. (Tue,) reported a other. Selective targeting of KCa1.1 αβ3 channels reduces invasiveness of RA synovial fibroblasts, suggesting a promising therapeutic approach for rheumatoid arthritis.
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