Kv1.3 Channel Up-Regulation in Peripheral Blood T Lymphocytes of Patients With Multiple Sclerosis

Abstract

Voltage-gated Kv1.3 potassium channels are key regulators of T lymphocyte activation, proliferation and cytokine production, by providing the necessary membrane hyper-polarization for calcium influx following immune stimulation. It is noteworthy that an accumulating body of in vivo and in vitro evidence links these channels to multiple sclerosis pathophysiology. Here we studied the electrophysiological properties and the transcriptional and translational expression of T lymphocyte Kv1.3 channels in multiple sclerosis, by combining patch clamp recordings, reverse transcription polymerase chain reaction and flow cytometry on freshly isolated peripheral blood T lymphocytes from two patient cohorts with multiple sclerosis, as well as from healthy and disease controls. Our data demonstrate that T lymphocytes in MS, manifest a significant up-regulation of Kv1.3 mRNA, Kv1.3 membrane protein and Kv1.3 current density and therefore of functional membrane channel protein, compared to control groups (p < 0.001). Interestingly, patient sub-grouping shows that Kv1.3 channel density is significantly higher in secondary progressive, compared to relapsing-remitting multiple sclerosis (p < 0.001). Taking into account the tight connection between Kv1.3 channel activity and calcium-dependent processes, our data predict and could partly explain the reported alterations of T lymphocyte function in multiple sclerosis, while they highlight Kv1.3 channels as potential therapeutic targets and peripheral biomarkers for the disease.

Characterization of endogenous Kv1.3 channel isoforms in T cells.

“…The expression of the three isoforms of Kv1.3 was extremely low in the resting state of Jurkat T cells and was upregulated after treatment with T cell activation stimuli (PMA+ionomycin, PHA-P and CD3+CD28) (Figure D3). This upregulation of Kv1.3 channel after antigen recognition was previously described in literature (87,122). Surprisingly, Thapsigargin (SERCA inhibitor) which was described as a proapoptotic stimuli for Jurkat T cells (123), was the strongest Kv1.3 up regulator of Kv1.3 isoforms, whereas other pro-apoptotic treatments had no effect on Kv1.3 expression.…”

“…We had previously confirmed that the basal expression of the three Kv1.3 isoforms in Jurkat was very low in resting conditions. Previous studies stated that Kv1.3 was involved in the activation and apoptosis pathways of T cells (87,122). We decided to study whether the expression of the channel could be upregulated by both pro-apoptotic and activating stimuli.…”

De novo variants in KCNA3 cause developmental and epileptic encephalopathy

“…Kv1.3 channels also provide a major contribution to voltage‐dependent K + currents in T‐lymphocytes, 4,17 where they regulate cell proliferation. Distinct expression patterns of Kv1.3 have been described in autoimmune disease 38,39 . Native currents recorded from individual #13‐derived lymphoblasts displayed mixed LoF/GoF effects when compared to those from the non‐carrier father‐derived cells; these effects were qualitatively similar to those found in the heterologous expression system.…”

Regulation of T Lymphocyte Functions through Calcium Signaling Modulation by Nootkatone

“…K V 1.3 and K Ca 3.1 channels are upregulated upon Ca 2+ influx into cytosol during cell activation, and dysregulation of potassium channels may also contribute to immune disorders [5,27]. For example, K V 1.3 channels are considered as therapeutic targets of autoimmune diseases like multiple sclerosis [28,29], while K Ca 3.1 is implicated in various autoimmune diseases and inflammation developments, including rheumatoid arthritis, asthma, T-cell mediated colitis, and vascular inflammation [30][31][32][33]. Both potassium channels represent potential pharmacological targets in these diseases [6,9,26].…”