Regulatory role of KCa3.1 in immune cell function and its emerging association with rheumatoid arthritis

Figures

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  Figure 1. Schematic representation of the structure of KCa3.1. A functional Ca2+-activated intermediate conductance K+ channel (KCa3.1) comprises four α subunits organized around a central pore through which K+ flows out of the cell. (A) KCa3.1 channel composed of four α subunits. (B) Top view of four α subunits around the central pore. (C) Schematic representation of a single KCa3.1 subunit, showing a total of 427 amino acids and consists of six transmembrane segments, named S1-S6. The K+ ion conduction pore is located between the loop and S6, containing the GYGD K+ channel pore sequence. CaM N-lobe binds to CAMBD2A and CAMBD2B with Ca2+, leading to channel opening. (Created with BioRender.com).

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  Figure 2. KCa3.1 regulates cytokine production and secretion. TGF-β1 binds to type II receptors and transphosphorylates type I receptors, phosphorylates Smad2/3 and secretes many inflammatory factors. Activation of KCa3.1 also promotes the secretion of IL-1β, IL-6, IL-8, TNF-α, and MCP-1 through the STAT3 and NF-κB signaling pathways. IFN-γ is upregulated by KCa3.1 either. KCa3.1 restrains the production of IL-10 through the JNK/c-Jun and NF-κB pathways. The blocked KCa3.1 channel by TRAM-34 inhibits these pathways. IL-17A is a pro-inflammatory cytokine that is upregulated by TRAM-34 through activation of KLF4 and/or TRIM33. (Created with BioRender.com).

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  Figure 3. Cytokines regulate KCa3.1 expression and activity. TGF-β1 inhibits catalase, thereby synthesizing hydrogen peroxide to activate KCa3.1. IL-4 and IL-1β upregulates AP-1 through JAK3/RAS/MEK/ERK and NF-κB signaling pathway, resulting in the initiation of KCa3.1 transcription. AP-1 can be upregulated by activated CaMKIV/CREB and p38 MAPK pathway, either. KCa3.1 activity is controlled by elevated cAMP in response to agents. (Created with BioRender.com).

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  Figure 4. Functions of KCa3.1 channel in the pathological process of rheumatoid arthritis. KCa3.1 is involved in RA inflammation, cartilage and bone destruction by regulating the abnormal activation of immune cells, synoviocytes and osteoclasts. Dashed arrows indicate possible mechanisms in rheumatoid arthritis. (Created with BioRender.com).