title: 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.
authors.affiliation: Department of Immunology Research, Merck Research Laboratories, Merck and Co., Rahway, NJ 07065, USA.
authors.forename: G C
authors.initials: GC
authors.lastname: Koo
authors.forename: J T
authors.initials: JT
authors.lastname: Blake
authors.forename: A
authors.initials: A
authors.lastname: Talento
authors.forename: M
authors.initials: M
authors.lastname: Nguyen
authors.forename: S
authors.initials: S
authors.lastname: Lin
authors.forename: A
authors.initials: A
authors.lastname: Sirotina
authors.forename: K
authors.initials: K
authors.lastname: Shah
authors.forename: K
authors.initials: K
authors.lastname: Mulvany
authors.forename: D
authors.initials: D
authors.lastname: Hora
authors.forename: P
authors.initials: P
authors.lastname: Cunningham
authors.forename: D L
authors.initials: DL
authors.lastname: Wunderler
authors.forename: O B
authors.initials: OB
authors.lastname: McManus
authors.forename: R
authors.initials: R
authors.lastname: Slaughter
authors.forename: R
authors.initials: R
authors.lastname: Bugianesi
authors.forename: J
authors.initials: J
authors.lastname: Felix
authors.forename: M
authors.initials: M
authors.lastname: Garcia
authors.forename: J
authors.initials: J
authors.lastname: Williamson
authors.forename: G
authors.initials: G
authors.lastname: Kaczorowski
authors.forename: N H
authors.initials: NH
authors.lastname: Sigal
authors.forename: M S
authors.initials: MS
authors.lastname: Springer
authors.forename: W
authors.initials: W
authors.lastname: Feeney
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D006968:Hypersensitivity, Delayed / Q000276:immunology*; D015640:Ion Channel Gating / Q000187:drug effects / Q000276:immunology; D008213:Lymphocyte Activation; D008564:Membrane Potentials / Q000276:immunology; D009498:Neurotoxins / Q000494:pharmacology; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000276:immunology*; D012604:Scorpion Venoms; D013552:Swine; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D009498:Neurotoxins; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D012604:Scorpion Venoms; C077910:margatoxin