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Archives of Toxicology

, Volume 89, Issue 7, pp 1119–1134 | Cite as

Potassium currents inhibition by gambierol analogs prevents human T lymphocyte activation

  • J. A. Rubiolo
  • C. Vale
  • V. Martín
  • H. Fuwa
  • M. Sasaki
  • L. M. Botana
Immunotoxicology

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.

Keywords

Gambierol Heptacyclic analog of gambierol Tetracyclic analog of gambierol Voltage-gated potassium channels Human T lymphocytes Ciguatoxin Autoimmune diseases 

Abbreviations

4-AP

4-Aminopyridine

TEA

Tetraethylammonium

Kv

Voltage-gated potassium channel

IKCa

Calcium-activated potassium channels

EDTA

Ethylenediaminetetraacetic acid

FBS

Fetal bovine serum

IL-2

Human interleukin 2

TRAM-34

1-[(2-Chlorophenyl)diphenylmethyl]-1H-pyrazole

Con

Concanavalin A

MTT

3-[4,5-Dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide

Notes

Acknowledgments

The research leading to these results has received funding from the following FEDER co-funded grants. From CDTI and Technological Funds, supported by Ministerio de Economía y Competitividad, AGL2012-40185-CO2-01 and Consellería de Cultura, Educación e Ordenación Universitaria, GRC2013-016, and through Axencia Galega de Innovación, Spain, ITC-20133020 SINTOX, IN852A 2013/16-3 MYTIGAL. From CDTI under ISIP Programme, Spain, IDI-20130304 APTAFOOD. From the European Union’s Seventh Framework Programme managed by REA – Research Executive Agency (FP7/2007-2013) under grant agreement Nos. 265409 µAQUA, 315285 CIGUATOOLS and 312184 PHARMASEA. Grants-in-Aid for Scientific Research on Priority Areas “Chemical Biology of Natural Products”: (Nos. 24102507 and 23102016) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan.

Supplementary material

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Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  1. 1.Departamento de Farmacología, Facultad de VeterinariaUniversidad de Santiago de CompostelaLugoSpain
  2. 2.Graduate School of Life SciencesTohoku UniversitySendaiJapan

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