Fighting rheumatoid arthritis: Kv1.3 as a therapeutic target

Serrano-Albarrás, Antonio; Cirera-Rocosa, Sergi; Sastre, Daniel; Estadella, Irene; Felipe, Antônio

doi:10.1016/j.bcp.2019.03.016

Cited by 25 publications

(15 citation statements)

References 103 publications

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“…Blockade of Kv1.3 inhibits the reactivity of these cells and ameliorates symptoms of psoriasis in animal models with no side effects. The researchers are trying to enhance the selectivity of the blockers, thereby reducing their side effects 96 .…”

Section: Magnolia Officinalis Contains a Biphenolicmentioning

confidence: 99%

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2021

IJPSR

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Psoriasis is a skin disorder marked with inflammation. The development and progression of the disease are associated with a chronic inflammatory response, which is attributed to the dysregulated innate immune system. The dendritic cells and T cells secrete various cytokines leading to disturbances in the keratinocyte proliferation and differentiation. Several medications are available for the mitigation of psoriasis. The currently used antipsoriatic medications are expensive; carry the threat of serious side-effects and frequent remission attacks of the disease. Exploring safer and effective antipsoriatic drugs remains still a major concern. Natural products represent important treatment options for psoriasis. This review article discusses studies related to the topical formulations of anti-psoriatic plants and plant products. The pathogenesis and clinical symptoms of psoriasis include multiple immunological mechanisms and pro-inflammatory cytokines. The review aims to summarize the research done in this area and to explain the mechanism of action of herbal medicines. The review article is aimed at opening new medical approaches for treating psoriasis. All the findings suggested that various herbal constituents are responsible for anti-psoriatic activity. Herbal medicines can be used as promising anti-psoriatic agents. The antipsoriatic effects of herbal medicines are through modulation of the signaling pathways of the cells. The phytoconstituents inhibit keratinocytes proliferation and differentiation by targeting different molecular targets. The results suggested the use of plants as a safe, effective, and inexpensive option for treating psoriasis.

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Section: Magnolia Officinalis Contains a Biphenolicmentioning

confidence: 99%

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2021

IJPSR

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“…Suppression of T cell activation can be achieved using conventional immunosuppressive drugs, such as cyclosporin A, tacrolimus (FK-506) and rapamycin (Halloran 2004). As these molecules target second messenger pathways that are common in immune cells, e.g., inhibition of calcineurin by cyclosporin A (Schreiber and Crabtree 1992), their application results in generalized immunosuppression. This means that inhibition of T cell activation and proliferation is not specific for a given autoantigen-induced T cell population, and as such, the treatment increases the risk of infections (Kim and Perfect 1989;Lallana and Fadul 2011;Orlicka et al 2013).…”

Section: Introductionmentioning

confidence: 99%

“…Furthermore, several neuroinflammatory diseases are proposed to be targeted by Kv1.3 inhibitors, including Alzheimer's disease, where inhibition of Kv1.3 expressed in microglia seems to be important (Nguyen et al 2017;Rangaraju et al 2015). Several extensive reviews have addressed the applicability of ion channel blockers in the management of autoimmune diseases (Chandy and Norton 2017;Norton and Chandy 2017;Panyi et al 2006;Serrano-Albarras et al 2019;Tajti et al 2020;Varga et al 2010;Wulff et al 2009).…”

Section: Introductionmentioning

confidence: 99%

The Kv1.3 K+ channel in the immune system and its “precision pharmacology” using peptide toxins

2021

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Since the discovery of the Kv1.3 voltage-gated K+ channel in human T cells in 1984, ion channels are considered crucial elements of the signal transduction machinery in the immune system. Our knowledge about Kv1.3 and its inhibitors is outstanding, motivated by their potential application in autoimmune diseases mediated by Kv1.3 overexpressing effector memory T cells (e.g., Multiple Sclerosis). High affinity Kv1.3 inhibitors are either small organic molecules (e.g., Pap-1) or peptides isolated from venomous animals. To date, the highest affinity Kv1.3 inhibitors with the best Kv1.3 selectivity are the engineered analogues of the sea anemone peptide ShK (e.g., ShK-186), the engineered scorpion toxin HsTx1[R14A] and the natural scorpion toxin Vm24. These peptides inhibit Kv1.3 in picomolar concentrations and are several thousand-fold selective for Kv1.3 over other biologically critical ion channels. Despite the significant progress in the field of Kv1.3 molecular pharmacology several progressive questions remain to be elucidated and discussed here. These include the conjugation of the peptides to carriers to increase the residency time of the peptides in the circulation (e.g., PEGylation and engineering the peptides into antibodies), use of rational drug design to create novel peptide inhibitors and understanding the potential off-target effects of Kv1.3 inhibition.

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“…The voltage-dependent potassium (Kv) channel Kv1.3, mainly expressed in the immune (T and B lymphocytes, macrophages and dendritic cells) and nervous (olfactory bulb and hippocampus) systems, contributes to the resting membrane potential. The role of Kv1.3 during the immune response and its aberrant behaviors in several autoimmune diseases indicate that this protein is an excellent target for immunomodulation [1][2][3][4].…”

Section: Introductionmentioning

confidence: 99%

“…In particular, KCNE4 associates with Kv1. 3 to control channel function [14,15]. KCNE4 not only impairs Kv1.3 trafficking and targeting to the plasma membrane but also modulates the activity of the channel, fine-tuning cellular responses [14].…”

Section: Introductionmentioning

confidence: 99%

Functional Consequences of the Variable Stoichiometry of the Kv1.3-KCNE4 Complex

Solé

Sastre

Colomer-Molera

et al. 2020

Cells

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The voltage-gated potassium channel Kv1.3 plays a crucial role during the immune response. The channel forms oligomeric complexes by associating with several modulatory subunits. KCNE4, one of the five members of the KCNE family, binds to Kv1.3, altering channel activity and membrane expression. The association of KCNEs with Kv channels is the subject of numerous studies, and the stoichiometry of such associations has led to an ongoing debate. The number of KCNE4 subunits that can interact and modulate Kv1.3 is unknown. KCNE4 transfers important elements to the Kv1.3 channelosome that negatively regulate channel function, thereby fine-tuning leukocyte physiology. The aim of this study was to determine the stoichiometry of the functional Kv1.3-KCNE4 complex. We demonstrate that as many as four KCNE4 subunits can bind to the same Kv1.3 channel, indicating a variable Kv1.3-KCNE4 stoichiometry. While increasing the number of KCNE4 subunits steadily slowed the activation of the channel and decreased the abundance of Kv1.3 at the cell surface, the presence of a single KCNE4 peptide was sufficient for the cooperative enhancement of the inactivating function of the channel. This variable architecture, which depends on KCNE4 availability, differentially affects Kv1.3 function. Therefore, our data indicate that the physiological remodeling of KCNE4 triggers functional consequences for Kv1.3, thus affecting cell physiology.

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Fighting rheumatoid arthritis: Kv1.3 as a therapeutic target

Cited by 25 publications

References 103 publications

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The Kv1.3 K+ channel in the immune system and its “precision pharmacology” using peptide toxins

Functional Consequences of the Variable Stoichiometry of the Kv1.3-KCNE4 Complex

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