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Review
. 2022 Oct 5:13:997621.
doi: 10.3389/fimmu.2022.997621. eCollection 2022.

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

Yi Lin  1   2 , Ying-Jie Zhao  1 , Hai-Lin Zhang  1   2 , Wen-Juan Hao  1   2 , Ren-Di Zhu  1   2 , Yan Wang  1   2 , Wei Hu  1   3 , Ren-Peng Zhou  1   3
Affiliations
Review

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

Yi Lin et al. Front Immunol. .

Abstract

Rheumatoid arthritis (RA) is a common autoimmune disease characterized by chronic inflammation. Immune dysfunction is an essential mechanism in the pathogenesis of RA and directly linked to synovial inflammation and cartilage/bone destruction. Intermediate conductance Ca2+-activated K+ channel (KCa3.1) is considered a significant regulator of proliferation, differentiation, and migration of immune cells by mediating Ca2+ signal transduction. Earlier studies have demonstrated abnormal activation of KCa3.1 in the peripheral blood and articular synovium of RA patients. Moreover, knockout of KCa3.1 reduced the severity of synovial inflammation and cartilage damage to a significant extent in a mouse collagen antibody-induced arthritis (CAIA) model. Accumulating evidence implicates KCa3.1 as a potential therapeutic target for RA. Here, we provide an overview of the KCa3.1 channel and its pharmacological properties, discuss the significance of KCa3.1 in immune cells and feasibility as a drug target for modulating the immune balance, and highlight its emerging role in pathological progression of RA.

Keywords: KCa3.1; immune cells; joint inflammation; rheumatoid arthritis; synovitis.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
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).
Figure 2
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).
Figure 3
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).
Figure 4
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).
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