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.

Wei-Ting Chang,Ping-Yen Liu,Sheng-Nan Wu

doi:10.3390/molecules25194525

Abstract

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.

Highlights

FTY720 (Fingolimod, Glienya®, 2-Amino-2-(2-[4-octylphenyl]ethyl)-1,3-propanediol) is a potent immunosuppressive agent that was originally derived from myriocin, a sphingosine-like fungalMolecules 2020, 25, 4525; doi:10.3390/molecules25194525 www.mdpi.com/journal/moleculesMolecules 2020, 25, 4525 metabolite [1,2]
FTY720 can act to work through its binding to S1P receptor subtype 1 (S1P1 ), which can prevent the egress of lymphocytes from lymph nodes [5,6]
The KV 1.3 phenotype has been previously demonstrated to be expressed in ion myelin-specific activated cells from patients with multiple sclerosis and not detected in T cells activated with other antigens [16]

Summary

Introduction

Molecules 2020, 25, 4525 metabolite [1,2] This compound is thought to possess encouraging efficacy profiles in different experimental autoimmune disorders and for the treatment of multiple sclerosis [1,3,4]. From another perspective, FTY720 can act to work through its binding to S1P receptor subtype 1 (S1P1 ), which can prevent the egress of lymphocytes from lymph nodes [5,6]. KV 1.3+ cells secrete considerable amounts of interferon-γ and tumor necrotic factor-α [17]

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