Blockade of the voltage-gated potassium channel Kv1.3 inhibits immune responses in vivo.

Abstract

The voltage activated K+ channel (Kv1.3) has recently been identified as the molecule that sets the resting membrane potential of peripheral human T lymphoid cells. In vitro studies indicate that blockage of Kv1.3 inhibits T cell activation, suggesting that Kv1.3 may be a target for immunosuppression. However, despite the in vitro evidence, there has been no in vivo demonstration that blockade of Kv1.3 will attenuate an immune response. The difficulty is due to species differences, as the channel does not set the membrane potential in rodent peripheral T cells. In this study, we show that the channel is present on peripheral T cells of miniswine. Using the peptidyl Kv1.3 inhibitor, margatoxin, we demonstrate that Kv1.3 also regulates the resting membrane potential, and that blockade of Kv1.3 inhibits, in vivo, both a delayed-type hypersensitivity reaction and an Ab response to an allogeneic challenge. In addition, prolonged Kv1.3 blockade causes reduced thymic cellularity and inhibits the thymic development of T cell subsets. These results provide in vivo evidence that Kv1.3 is a novel target for immunomodulation.

Transcriptome‐wide summary data‐based Mendelian randomization analysis reveals 38 novel genes associated with severe COVID‐19

“…Two of the top 10 genes, KCNC3 and PLEKHM1 , are novel genes associated with severe COVID‐19 and may play a causal role in the disease through the immune system. KCNC3 is a gated potassium voltage channel that may affect the immune response by inhibiting T cell activation 44 . PLEKHM1 regulates autophagosome‐lysosome fusion, and depletion of PLEKHM1 enhances the presentation of MHC class 1 molecules, thereby affecting the immune response 45 .…”

Purlisin, a toxin‐like defensin derived from clinical pathogenic fungus Purpureocillium lilacinum with both antimicrobial and potassium channel inhibitory activities

“…S aureus and S epidermidis are two of the most common colonization bacteria of skin 47,48 . The h Kv1.3 channel has been recognized as a target for regulating immunity, and blockade of this kind of potassium channel can inhibit immune responses in vivo 49 . Therefore, the toxin‐like fungal defensin of purlisin with both potassium channel‐blocking activities (purlisin‐NT) and antimicrobial effects (purlisin‐CT) might contribute to the pathogenic mechanism of the invasive P lilacinum infection.…”

Potassium Channels in Parkinson’s Disease: Potential Roles in Its Pathogenesis and Innovative Molecular Targets for Treatment

“…Another category of K V 1.3 inhibitors has been developed from peptide toxins, such as scorpion toxins (e.g., Charybdotoxin (ChTx), Margatoxin (MgTx), Agitoxin 2 (AgTx-2), α-KTx3.7 (OsK-1), and snake toxins (e.g., BF9) (Bartok et al, 2014;Chen et al, 2001;Mouhat et al, 2005;Pimentel et al, 2008). These peptidic K V and in vivo studies to demonstrate the potential therapeutic effects of blocking K V 1.3mediated K + currents in different disease models, including PD (Koo et al, 1997;Tubert et al, 2016;Yang et al, 2014a). One prominent example is ShK, a 35-residue disulfide-rich peptide toxin purified from the sea anemone, Stichodactyla helianthus (Norton et al, 2004;Tudor et al, 1996).…”