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E–G) Flow cytometric analysis of surface expression of total β 1 integrins ( E), activated β 1 integrins ( F), and α 4-6 integrins ( G) by RA-FLSs plated on fibronectin-coated plates for 1 h in presence of either DMSO or paxilline. D) Adhesion of RA-FLSs in presence of DMSO (control), paxilline (20 µM), soluble RGD peptides (150 μg/ml), or combination of paxilline and RGD peptides n = 3 RA-FLS donors per group. C) Adhesion of RA-FLSs in presence of DMSO (vehicle, control) or KCa1.1 opener phloretin (100 µM) n = 3 donors per group. Data are provided as means ± sem n = 3 donors per group. B) Adhesion of RA-FLSs in saline solution containing 25 mM potassium. A) Adhesion of RA-FLSs to integrin-dependent and -independent substrates in presence of DMSO (vehicle, control), or KCa1.1 blockers paxilline (pax 20 µM), or iberiotoxin (IbTX 10 µM) for 1 h before analysis n = 3 donors per group. KCa1.1 modulation alters RA-FLS adhesion and β 1-integrin expression. KCa1.1 channels regulate β 1-integrin function and cell adhesion in rheumatoid arthritis fibroblast-like synoviocytes. Together, these data outline a new signaling mechanism by which KCa1.1 regulates β 1-integrin function and therefore invasiveness of RA-FLSs.-Tanner, M. Interestingly, the pore-forming α subunit of KCa1.1 coimmunoprecipitates with β 1 integrins, suggesting that this physical association underlies the functional interaction between these molecules. Blocking KCa1.1 disturbs calcium homeostasis, leading to the sustained phosphorylation of Akt and the recruitment of talin to β 1 integrins. Here, we demonstrate that KCa1.1 regulates RA-FLS adhesion through controlling the plasma membrane expression and activation of β 1 integrins, but not α 4, α 5, or α 6 integrins.

However, the molecular mechanisms by which KCa1.1 regulates RA-FLS invasiveness have remained largely unknown. It is a critical regulator of RA-FLS migration and invasion and therefore represents an attractive target for the therapy of RA. Large-conductance calcium-activated potassium channel (KCa1.1 BK, Slo1, MaxiK, KCNMA1) is the predominant potassium channel expressed at the plasma membrane of rheumatoid arthritis fibroblast-like synoviocytes (RA-FLSs) isolated from the synovium of patients with RA.