Understanding autoimmunity: The ion channel perspective

Ramakrishnan, Anantha Maharasi; Kannan, Sankaranarayanan

doi:10.1016/j.autrev.2016.02.004

Cited by 18 publications

(16 citation statements)

References 425 publications

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“…Despite this attraction and the demonstrated involvement of ion channel antibodies in diverse autoimmune diseases 2 , no antibody-based ion channel therapeutic has progressed to the clinic, due to challenges in developing both optimal immunogens and robust screening processes to identify channel modulators 3 .…”

Section: Introductionmentioning

confidence: 99%

Evaluation of recombinant monoclonal antibody SVmab1 binding to NaV1.7 target sequences and block of human NaV1.7 currents

et al. 2016

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Identification of small and large molecule pain therapeutics that target the genetically validated voltage-gated sodium channel Na V1.7 is a challenging endeavor under vigorous pursuit. The monoclonal antibody SVmab1 was recently published to bind the Na V1.7 DII voltage sensor domain and block human Na V1.7 sodium currents in heterologous cells. We produced purified SVmab1 protein based on publically available sequence information, and evaluated its activity in a battery of binding and functional assays. Herein, we report that our recombinant SVmAb1 does not bind peptide immunogen or purified Na V1.7 DII voltage sensor domain via ELISA, and does not bind Na V1.7 in live HEK293, U-2 OS, and CHO-K1 cells via FACS. Whole cell manual patch clamp electrophysiology protocols interrogating diverse Na V1.7 gating states in HEK293 cells, revealed that recombinant SVmab1 does not block Na V1.7 currents to an extent greater than observed with an isotype matched control antibody. Collectively, our results show that recombinant SVmab1 monoclonal antibody does not bind Na V1.7 target sequences or specifically inhibit Na V1.7 current.

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Section: Introductionmentioning

confidence: 99%

Evaluation of recombinant monoclonal antibody SVmab1 binding to NaV1.7 target sequences and block of human NaV1.7 currents

et al. 2016

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“…FTY720 has indeed been reported to mediate cytochrome c release from mitochondria in rat thymocytes [ 34 ]. Nonetheless, because of the importance of I K(DR) (i.e., K V 1.3-encoded current) in contributing to functional activities of lymphocytes such as apoptosis [ 12 , 34 ], the effects of FTY720 presented herein could provide novel insights into pharmacological or immunological properties of FTY720 and other structurally related compounds [ 15 , 35 ].…”

Section: Discussionmentioning

confidence: 99%

“…The K V 1.3-encoded currents, which exhibit unique gating properties and voltage dependency, largely constitute the delayed-rectifier K + currents ( I K(DR ) enriched in immune cells [ 9 , 10 , 11 ]. These currents, which can be functionally expressed in the plasma membrane and the inner mitochondrial membrane, have been demonstrated to perform key functions in the immune system such as lymphocyte activation [ 10 , 11 , 12 , 13 , 14 , 15 ]. In particular, the K V 1.3 phenotype has been previously demonstrated to be specifically expressed in ion myelin-specific activated cells from patients with multiple sclerosis and not detected in T cells activated with other antigens [ 16 ].…”

Section: Introductionmentioning

confidence: 99%

“…K V 1.3 + cells secrete considerable amounts of interferon-γ and tumor necrotic factor-α [ 17 ] and K V 1.3 inhibitors potently suppress experimental autoimmune encephalitis [ 18 , 19 ]. The inhibitors of K V 1.3 channels indeed represent a potentially therapeutic approach to the diseases including multiple sclerosis [ 2 , 4 , 15 ]. Additionally, it was noticed that the activity of intermediated-conductance Ca 2+ -activated K + channels (i.e., KCa3.1-encoded channels) was functionally expressed in immune cells [ 20 , 21 ].…”

Section: Introductionmentioning

confidence: 99%

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Actions of FTY720 (Fingolimod), a Sphingosine-1-Phosphate Receptor Modulator, on Delayed-Rectifier K+ Current and Intermediate-Conductance Ca2+-Activated K+ Channel in Jurkat T-Lymphocytes

Chang

Liu

2020

Molecules

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FTY720 (fingolimod), a modulator of sphingosine-1-phosphate receptors, is known to produce the immunomodulatory actions and to be beneficial for treating the relapsing multiple sclerosis. However, whether it exerts any effects on membrane ion currents in immune cells remains largely unknown. Herein, the effects of FTY720 on ionic currents in Jurkat T-lymphocytes were investigated. Cell exposure to FTY720 suppressed the amplitude of delayed-rectifier K+ current (IK(DR)) in a time- and concentration-dependent manner with an IC50 value of 1.51 μM. Increasing the FTY720 concentration not only decreased the IK(DR) amplitude but also accelerated the inactivation time course of the current. By using the minimal reaction scheme, the effect of FTY720 on IK(DR) inactivation was estimated with a dissociation constant of 3.14 μM. FTY720 also shifted the inactivation curve of IK(DR) to a hyperpolarized potential with no change in the slope factor, and recovery from IK(DR) became slow during the exposure to this compound. Cumulative inactivation for IK(DR) in response to repetitive depolarizations was enhanced in the presence of FTY720. In SEW2871-treated cells, FTY720-induced inhibition of IK(DR) was attenuated. This compound also exerted a stimulatory action on the activity of intermediate-conductance Ca2+-activated K+ channels in Jurkat T-lymphocytes. However, in NSC-34 neuronal cells, FTY720 did not modify the inactivation kinetics of KV3.1-encoded IK(DR), although it suppressed IK(DR) amplitude in these cells. Collectively, the perturbations by FTY720 on different types of K+ channels may contribute to the functional activities of immune cells, if similar findings appear in vivo.

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“…Ion channels genes, whose expression changes following GA treatment, belong the repertoire of ion-conducting proteins like potassium and chloride, Ca 2+ release-activated Ca 2+ (CRAC) and TRP channels. These last channels participate to ER Ca 2+ refilling 17,18 which represents the major Ca 2+ influx mechanism in B lymphocytes controlling antigen-mediated lymphocyte activation, cytokine/chemokine production, exocytosis, enzyme control, proliferation and apoptosis 19–21 . In line with the bioinformatic findings, intracellular Ca 2+ concentration was reduced in vitro by GA but increased ex vivo .…”

Section: Discussionmentioning

confidence: 99%

Glatiramer Acetate modulates ion channels expression and calcium homeostasis in B cell of patients with relapsing-remitting multiple sclerosis

Criscuolo

Cianflone

Lanzillo

et al. 2019

Sci Rep

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To investigate the effects of Glatiramer Acetate (GA) on B cells by an integrated computational and experimental approach. GA is an immunomodulatory drug approved for the treatment of multiple sclerosis (MS). GA effect on B cells is yet to be fully elucidated. We compared transcriptional profiles of B cells from treatment-naïve relapsing remitting MS patients, treated or not with GA for 6 hours in vitro, and of B cells before and after six months of GA administration in vivo. Microarrays were analyzed with two different computational approaches, one for functional analysis of pathways (Gene Set Enrichment Analysis) and one for the identification of new drug targets (Mode-of-action by Network Analysis). GA modulates the expression of genes involved in immune response and apoptosis. A differential expression of genes encoding ion channels, mostly regulating Ca2+ homeostasis in endoplasmic reticulum (ER) was also observed. Microfluorimetric analysis confirmed this finding, showing a specific GA effect on ER Ca2+ concentration. Our findings unveils a GA regulatory effect on the immune response by influencing B cell phenotype and function. In particular, our results highlight a new functional role for GA in modulating Ca2+ homeostasis in these cells.

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Understanding autoimmunity: The ion channel perspective

Cited by 18 publications

References 425 publications

Evaluation of recombinant monoclonal antibody SVmab1 binding to NaV1.7 target sequences and block of human NaV1.7 currents

Evaluation of recombinant monoclonal antibody SVmab1 binding to NaV1.7 target sequences and block of human NaV1.7 currents

Actions of FTY720 (Fingolimod), a Sphingosine-1-Phosphate Receptor Modulator, on Delayed-Rectifier K+ Current and Intermediate-Conductance Ca2+-Activated K+ Channel in Jurkat T-Lymphocytes

Glatiramer Acetate modulates ion channels expression and calcium homeostasis in B cell of patients with relapsing-remitting multiple sclerosis

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