title: Potassium currents inhibition by gambierol analogs prevents human T lymphocyte activation.
abstract: Gambierol is a marine polycyclic ether toxin, produced along with ciguatoxin congeners by the dinoflagellate Gambierdiscus toxicus. We have recently reported that two truncated skeletal analogs of gambierol comprising the EFGH- and BCDEFGH-rings of the parent compound showed similar potency to gambierol on voltage-gated potassium channels (Kv) inhibition in neurons. Gambierol and its truncated analogs share the main crucial elements for biological activity, which are the C28=C29 double bond within the H-ring and the unsaturated side chain. Since Kv channels are critical for the regulation of calcium signaling, proliferation, secretion and migration in human T lymphocytes, we evaluated the activity of both the tetracyclic and heptacyclic analogs of gambierol on potassium currents in resting T lymphocyte and their effects on interleukin-2 (IL-2) release and gene expression in activated T lymphocytes. The results presented in this work clearly demonstrate that both truncated analogs of gambierol inhibit Kv channels present in resting T lymphocytes (Kv1.3) and prevented lymphocyte activation by concanavalin A. The main effects of the heptacyclic and tetracyclic analogs of gambierol in human T cells are: (1) inhibition of potassium channels in resting and concanavalin-activated T cells in the nanomolar range, (2) inhibition of IL-2 release from concanavalin-activated T cells and (3) negatively affect the expression of genes involved in cell proliferation and immune response observed in concanavalin-activated lymphocytes. These results together with the lack of toxicity in this cellular model, indicates that both analogs of gambierol have additional potential for the development of therapeutic tools in autoimmune diseases.
authors.affiliation: Departamento de Farmacología, Facultad de Veterinaria, Universidad de Santiago de Compostela, 27003, Lugo, Spain.
authors.forename: J A
authors.initials: JA
authors.lastname: Rubiolo
authors.forename: C
authors.initials: C
authors.lastname: Vale
authors.forename: V
authors.initials: V
authors.lastname: Martín
authors.forename: H
authors.initials: H
authors.lastname: Fuwa
authors.forename: M
authors.initials: M
authors.lastname: Sasaki
authors.forename: L M
authors.initials: LM
authors.lastname: Botana
mesh_terms: D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002922:Ciguatoxins / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation; D006801:Humans; D007376:Interleukin-2 / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects*; D018942:Macrolides / Q000494:pharmacology; D008564:Membrane Potentials; D011188:Potassium / Q000378:metabolism*; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D024642:Potassium Channels, Voltage-Gated / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D035964:Oxocins
chemical_list: D002922:Ciguatoxins; D007376:Interleukin-2; D018942:Macrolides; D011188:Potassium; D026902:Potassium Channel Blockers; D024642:Potassium Channels, Voltage-Gated; C508594:IL2 protein, human; C435770:gambierol; D035964:Oxocins; C036978:concanamycin A