KCa1.1 channels as therapeutic targets for rheumatoid arthritis

Beeton, Christine

doi:10.1080/14728222.2017.1398234

Cited by 10 publications

(6 citation statements)

References 25 publications

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“…Fibroblast-like synoviocytes (FLS) are resident synovial joint cells that develop a highly invasive phenotype during RA, contributing to joint damage, and secrete a variety of proinflammatory cytokines and chemokines [14, 15]. We have previously demonstrated that FLS from patients with RA and from animal models of RA upregulate the potassium channel KCa1.1 at their plasma membrane [16–20]. KCa1.1 blockade with selective inhibitors, such as the fungal alkaloid paxilline and the Buthus tamulus scorpion venom toxin iberiotoxin (IbTX), reduces FLS invasion and cytokine and chemokine secretion ex vivo [17, 19, 21].…”

Section: Introductionmentioning

confidence: 99%

KCa1.1 and Kv1.3 channels regulate the interactions between fibroblast-like synoviocytes and T lymphocytes during rheumatoid arthritis

et al. 2019

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BackgroundFibroblast-like synoviocytes (FLS) and CCR7− effector memory T (TEM) cells are two of the major cell types implicated in the progression of rheumatoid arthritis (RA). In particular, FLS become highly invasive, whereas TEM cells proliferate and secrete proinflammatory cytokines, during RA. FLS and T cells may also interact and influence each other’s phenotypes. Inhibition of the pathogenic phenotypes of both FLS and TEM cells can be accomplished by selectively blocking the predominant potassium channels that they upregulate during RA: KCa1.1 (BK, Slo1, MaxiK, KCNMA1) upregulated by FLS and Kv1.3 (KCNA3) upregulated by activated TEM cells. In this study, we investigated the roles of KCa1.1 and Kv1.3 in regulating the interactions between FLS and TEM cells and determined if combination therapies of KCa1.1- and Kv1.3-selective blockers are more efficacious than monotherapies in ameliorating disease in rat models of RA.MethodsWe used in vitro functional assays to assess the effects of selective KCa1.1 and Kv1.3 channel inhibitors on the interactions of FLS isolated from rats with collagen-induced arthritis (CIA) with syngeneic TEM cells. We also used flow cytometric analyses to determine the effects of KCa1.1 blockers on the expression of proteins used for antigen presentation on CIA-FLS. Finally, we used the CIA and pristane-induced arthritis models to determine the efficacy of combinatorial therapies of KCa1.1 and Kv1.3 blockers in reducing disease severity compared with monotherapies.ResultsWe show that the interactions of FLS from rats with CIA and of rat TEM cells are regulated by KCa1.1 and Kv1.3. Inhibiting KCa1.1 on FLS reduces the ability of FLS to stimulate TEM cell proliferation and migration, and inhibiting Kv1.3 on TEM cells reduces TEM cells’ ability to enhance FLS expression of KCa1.1 and major histocompatibility complex class II protein, as well as stimulates their invasion. Furthermore, we show that combination therapies of selective KCa1.1 and Kv1.3 blockers are more efficacious than monotherapies at reducing signs of disease in two rat models of RA.ConclusionsOur results demonstrate the importance of KCa1.1 and Kv1.3 in regulating FLS and TEM cells during RA, as well as the value of combined therapies targeting both of these cell types to treat RA.Electronic supplementary materialThe online version of this article (10.1186/s13075-018-1783-9) contains supplementary material, which is available to authorized users.

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Section: Introductionmentioning

confidence: 99%

KCa1.1 and Kv1.3 channels regulate the interactions between fibroblast-like synoviocytes and T lymphocytes during rheumatoid arthritis

et al. 2019

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“…In addition, joint-resident fibroblast-like synoviocytes express the KCa1.1 channel (a.k.a. BK, Maxi-K or Slo1), and blocking this channel stops disease progression in CIA ( 27 ). We therefore tested ShK-235 for its ability to block either KCa3.1 or KCa1.1.…”

Section: Resultsmentioning

confidence: 99%

A bioengineered probiotic for the oral delivery of a peptide Kv1.3 channel blocker to treat rheumatoid arthritis

Wang

Zhu

Ortiz-Velez³

et al. 2023

Proc. Natl. Acad. Sci. U.S.A.

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Engineered microbes for the delivery of biologics are a promising avenue for the treatment of various conditions such as chronic inflammatory disorders and metabolic disease. In this study, we developed a genetically engineered probiotic delivery system that delivers a peptide to the intestinal tract with high efficacy. We constructed an inducible system in the probiotic Lactobacillus reuteri to secrete the Kv1.3 potassium blocker ShK-235 (LrS235). We show that LrS235 culture supernatants block Kv1.3 currents and preferentially inhibit human T effector memory (T EM ) lymphocyte proliferation in vitro. A single oral gavage of healthy rats with LrS235 resulted in sufficient functional ShK-235 in the circulation to reduce inflammation in a delayed-type hypersensitivity model of atopic dermatitis mediated by T EM cells. Furthermore, the daily oral gavage of LrS235 dramatically reduced clinical signs of disease and joint inflammation in rats with a model of rheumatoid arthritis without eliciting immunogenicity against ShK-235. This work demonstrates the efficacy of using the probiotic L. reuteri as a novel oral delivery platform for the peptide ShK-235 and provides an efficacious strategy to deliver other biologics with great translational potential.

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“…In synovial tissues, the role of BK channels has primarily been investigated in the context of RA. K Ca 1.1 channels have recently emerged as a broadly investigated therapeutic target for RA [ 174 ]. Besides immune cells, resident FLSs play a pivotal role in RA pathogenesis [ 175 ].…”

Section: Calcium-dependent Potassium Channelsmentioning

confidence: 99%

“…BK channels have been well documented to play a pivotal role in regulating several physiological processes including musculoskeletal homeostasis, neuronal excitability, and pain signalling. Thus, their therapeutic potential may be of particular interest for clinical practice [ 174 , 194 ].…”

Section: K Ca Channels In Musculoskeletal Pathologiesmentioning

confidence: 99%

Ca2+-Activated K+ Channels in Progenitor Cells of Musculoskeletal Tissues: A Narrative Review

Takács

Kovács

Ebeid

et al. 2023

IJMS

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Musculoskeletal disorders represent one of the main causes of disability worldwide, and their prevalence is predicted to increase in the coming decades. Stem cell therapy may be a promising option for the treatment of some of the musculoskeletal diseases. Although significant progress has been made in musculoskeletal stem cell research, osteoarthritis, the most-common musculoskeletal disorder, still lacks curative treatment. To fine-tune stem-cell-based therapy, it is necessary to focus on the underlying biological mechanisms. Ion channels and the bioelectric signals they generate control the proliferation, differentiation, and migration of musculoskeletal progenitor cells. Calcium- and voltage-activated potassium (KCa) channels are key players in cell physiology in cells of the musculoskeletal system. This review article focused on the big conductance (BK) KCa channels. The regulatory function of BK channels requires interactions with diverse sets of proteins that have different functions in tissue-resident stem cells. In this narrative review article, we discuss the main ion channels of musculoskeletal stem cells, with a focus on calcium-dependent potassium channels, especially on the large conductance BK channel. We review their expression and function in progenitor cell proliferation, differentiation, and migration and highlight gaps in current knowledge on their involvement in musculoskeletal diseases.

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KCa1.1 channels as therapeutic targets for rheumatoid arthritis

Cited by 10 publications

References 25 publications

KCa1.1 and Kv1.3 channels regulate the interactions between fibroblast-like synoviocytes and T lymphocytes during rheumatoid arthritis

KCa1.1 and Kv1.3 channels regulate the interactions between fibroblast-like synoviocytes and T lymphocytes during rheumatoid arthritis

A bioengineered probiotic for the oral delivery of a peptide Kv1.3 channel blocker to treat rheumatoid arthritis

Ca2+-Activated K+ Channels in Progenitor Cells of Musculoskeletal Tissues: A Narrative Review

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