Targeting synovial fibroblast KCa1.1 channels in rheumatoid arthritis

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.