title: Potent suppression of Kv1.3 potassium channel and IL-2 secretion by diphenyl phosphine oxide-1 in human T cells.
abstract: Diphenyl phosphine oxide-1 (DPO-1) is a potent Kv1.5 channel inhibitor that has therapeutic potential for the treatment of atrial fibrillation. Many other Kv1.5 channel blockers also potently inhibit the Kv1.3 channel, but whether DPO-1 blocks Kv1.3 channels has not been investigated. The Kv1.3 channel is highly expressed in activated T cells, which is considered a favorable target for immunomodulation. Accordingly, we hypothesized that DPO-1 may exert immunosuppressive and anti-inflammatory effects by inhibiting Kv1.3 channel activity. In this study, DPO-1 blocked Kv1.3 current in a voltage-dependent and concentration-dependent manner, with IC₅₀ values of 2.58 µM in Jurkat cells and 3.11 µM in human peripheral blood T cells. DPO-1 also accelerated the inactivation rate and negatively shifted steady-state inactivation. Moreover, DPO-1 at 3 µM had no apparent effect on the Ca²⁺ activated potassium channel (K(Ca)) current in both Jurkat cells and human peripheral blood T cells. In Jurkat cells, pre-treatment with DPO-1 for 24 h decreased Kv1.3 current density, and protein expression by 48±6% and 60±9%, at 3 and 10 µM, respectively (both p<0.05). In addition, Ca²⁺ influx to Ca²⁺-depleted cells was blunted and IL-2 production was also reduced in activated Jurkat cells. IL-2 secretion was also inhibited by the Kv1.3 inhibitors margatoxin and charybdotoxin. Our results demonstrate for the first time that that DPO-1, at clinically relevant concentrations, blocks Kv1.3 channels, decreases Kv1.3 channel expression and suppresses IL-2 secretion. Therefore, DPO-1 may be a useful treatment strategy for immunologic disorders.
authors.affiliation: Research Center of Ion Channelopathy, Institute of Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P.R. China.
authors.forename: Ning
authors.initials: N
authors.lastname: Zhao
authors.forename: Qian
authors.initials: Q
authors.lastname: Dong
authors.forename: Li-Li
authors.initials: LL
authors.lastname: Du
authors.forename: Xiao-Xing
authors.initials: XX
authors.lastname: Fu
authors.forename: Yi-Mei
authors.initials: YM
authors.lastname: Du
authors.forename: Yu-Hua
authors.initials: YH
authors.lastname: Liao
mesh_terms: D006801:Humans; D020128:Inhibitory Concentration 50; D007376:Interleukin-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019169:Jurkat Cells; D051664:Kv1.3 Potassium Channel / Q000037:antagonists & inhibitors*; D010720:Phosphines / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000187:drug effects*
chemical_list: C507236:(2-isopropyl-5-methylcyclohexyl) diphenylphosphine oxide; D007376:Interleukin-2; D051664:Kv1.3 Potassium Channel; D010720:Phosphines