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A polyether biotoxin binding site on the lipid-exposed face of the pore domain of Kv channels revealed by the marine toxin gambierol
Kopljar, I.; Labro, A.J.; Cuypers, E.; Johnson, H.W.B.; Rainier, J.D.; Tytgat, J.; Snyders, D.J. (2009). A polyether biotoxin binding site on the lipid-exposed face of the pore domain of Kv channels revealed by the marine toxin gambierol. Proc. Natl. Acad. Sci. U.S.A. 106(24): 9896-9901. http://dx.doi.org/10.1073/pnas.0812471106
In: Proceedings of the National Academy of Sciences of the United States of America. The Academy: Washington, D.C.. ISSN 0027-8424; e-ISSN 1091-6490, meer
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ciguatera neurotoxin site 5 polycyclic ether toxin potassium channels Kv3.1 |
| Auteurs | | Top |
- Kopljar, I., meer
- Labro, A.J., meer
- Cuypers, E., meer
- Johnson, H.W.B.
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- Rainier, J.D.
- Tytgat, J., meer
- Snyders, D.J., meer
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| Abstract |
Gambierol is a marine polycyclic ether toxin belonging to the group of ciguatera toxins. It does not activate voltage-gated sodium channels (VGSCs) but inhibits Kv1 potassium channels by an unknown mechanism. While testing whether Kv2, Kv3, and Kv4 channels also serve as targets, we found that Kv3.1 was inhibited with an IC50 of 1.2 ± 0.2 nM, whereas Kv2 and Kv4 channels were insensitive to 1 µM gambierol. Onset of block was similar from either side of the membrane, and gambierol did not compete with internal cavity blockers. The inhibition did not require channel opening and could not be reversed by strong depolarization. Using chimeric Kv3.1–Kv2.1 constructs, the toxin sensitivity was traced to S6, in which T427 was identified as a key determinant. In Kv3.1 homology models, T427 and other molecular determinants (L348, F351) reside in a space between S5 and S6 outside the permeation pathway. In conclusion, we propose that gambierol acts as a gating modifier that binds to the lipid-exposed surface of the pore domain, thereby stabilizing the closed state. This site may be the topological equivalent of the neurotoxin site 5 of VGSCs. Further elucidation of this previously undescribed binding site may explain why most ciguatoxins activate VGSCs, whereas others inhibit voltage-dependent potassium (Kv) channels. This previously undescribed Kv neurotoxin site may have wide implications not only for our understanding of channel function at the molecular level but for future development of drugs to alleviate ciguatera poisoning or to modulate electrical excitability in general. |
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