The lymphocyte potassium channels Kv1.3 and KCa3.1 as targets for immunosuppression

Abstract

The voltage-gated Kv1.3 and the calcium-activated KCa3.1 potassium channel modulate many calcium-dependent cellular processes in immune cells, including T-cell activation and proliferation, and have therefore been proposed as novel therapeutic targets for immunomodulation. Kv1.3 is highly expressed in CCR7− effector memory T cells and is emerging as a target for T-cell mediated diseases like multiple sclerosis, rheumatoid arthritis, type-1 diabetes mellitus, allergic contact dermatitis, and psoriasis. KCa3.1 in contrast is expressed in CCR7+ naïve and central memory T cells, as well as in mast cells, macrophages, dedifferentiated vascular smooth muscle cells, fibroblasts, vascular endothelium, and airway epithelium. Given this expression pattern, KCa3.1 is a potential therapeutic target for conditions ranging from inflammatory bowel disease, multiple sclerosis, arthritis, and asthma to cardiovascular diseases like atherosclerosis and post-angioplasty restenosis. Results from animal studies have been supportive of the therapeutic potential of both Kv1.3 and KCa3.1 blockers and have also not shown any toxicities associated with pharmacological Kv1.3 and KCa3.1 blockade. To date, two compounds targeting Kv1.3 are in preclinical development but, so far, no Kv1.3 blocker has advanced into clinical trials. KCa3.1 blockers, on the other hand, have been evaluated in clinical trials for sickle cell anemia and exercise-induced asthma, but have so far not shown efficacy. However, the trial results support KCa3.1 as a safe therapeutic target, and will hopefully help enable clinical trials for other medical conditions that might benefit from KCa3.1 blockade.

Immunosuppression by N-Methyl-d-Aspartate Receptor Antagonists Is Mediated through Inhibition of Kv1.3 and KCa3.1 Channels in T Cells

“…All inhibitors strongly blocked K v 1.3 channel currents, but in the case of D-APV, about 10-fold-higher concentrations were needed to obtain inhibition similar to that with ifenprodil. Thus, the employed concentrations of NMDAR antagonists, which were similar to those used previously by others (9), nonspecifically inhibited two potassium channels expressed on T cells, which reportedly modulate many Ca 2ϩ -mediated processes in T cells (34).…”

“…K v 1.3 and K Ca 3.1 channels provide the counterbalancing K ϩ efflux needed for Ca 2ϩ influx upon TCR ligation (34,35,50). Their blockade inhibits T-cell function and ameliorates various diseases, including experimental autoimmune encephalitis and allergic inflammatory lung diseases (42,45,51).…”

“…In view of the above-described findings and the strong effects of NMDAR pharmacology on Ca 2ϩ -dependent signaling, we hypothesized that the effects of NMDAR antagonists on the TCRinduced Ca 2ϩ signal involve K v 1.3 and K Ca 3.1 potassium channels. These channels regulate T-cell activation by controlling membrane potential and, hence, Ca 2ϩ flux into T cells (9,(33)(34)(35). Indeed, current-clamp recordings of CD3 plus CD28 Ab-activated CD4 ϩ T cells showed that ifenprodil (30 M) and memantine (50 M) depolarized the membrane potential from ϳϪ50 mV to ϳϪ15 mV and ϳϪ20 mV, respectively (data not shown).…”

Targeting ion channels for the treatment of autoimmune neuroinflammation

“…Smaller companies collaborating with scientists active in this research field [Airmid (www.airmid.com) and Kineta Inc. (www.kinetabio.com)] as well as larger pharmaceutical companies (e.g. Amgen and Evotec) are performing preclinical studies with different K V 1.3 blockers [Lam and Wulff, 2011]. However, none of these substances has so far advanced into clinical trials.…”

Kv1.3 channel blockade enhances the phagocytic function of RAW264.7 macrophages

“…Similar to that in excitable cells, changes in the membrane potential are among the earliest events that occur in re-sponse to stimulation [7] and thereby affect the functional activation state of macrophages. Various ion channels has been reported in macrophages, including Kv1.3 [8], Kv1.5 [8], inwardly rectifying K + channel 2.1 (Kir2.1) [7], KCa3.1 [9], CRAC [10], transient receptor potential cation (TRPC) channel [11], and voltage-gated proton (hydrogen) channels (HVCN) [12]. Among these channels, the Kv channels play a pivotal role in the modulation of macrophage physiology [13].…”