Antillatoxin is a sodium channel activator that displays unique efficacy in heterologously expressed rNav1.2, rNav1.4 and rNav1.5 alpha subunits

BMC Neuroscience

Research Article

William H Gerwick¹  Thomas F Murray²  Zhengyu Cao³ 

[1] Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, University of California at San Diego, 92093-0212, La Jolla, California, USA;Department of Pharmacology, Creighton University, School of Medicine, 68178, Omaha, NE, USA;Department of Pharmacology, Creighton University, School of Medicine, 68178, Omaha, NE, USA;Department of Molecular Biosciences, School of Veterinary Medicine, University of California at Davis, 95616, Davis, California, USA;

关键词: Sodium Channel;    Marine Cyanobacterium;    Neocortical Neuron;    Scorpion Toxin;    Allosteric Interaction;   

DOI  :  10.1186/1471-2202-11-154

 received in 2010-10-22, accepted in 2010-12-14,  发布年份 2010

来源: Springer

【 摘 要 】

BackgroundAntillatoxin (ATX) is a structurally unique lipopeptide produced by the marine cyanobacterium Lyngbya majuscula. ATX activates voltage-gated sodium channel α-subunits at an undefined recognition site and stimulates sodium influx in neurons. However, the pharmacological properties and selectivity of ATX on the sodium channel α-subunits were not fully characterized.ResultsIn this study, we characterized the pharmacological properties and selectivity of ATX in cells heterologously expressing rNav1.2, rNav1.4 or rNav1.5 α-subunits by using the Na+ selective fluorescent dye, sodium-binding benzofuran isophthalate. ATX produced sodium influx in cells expressing each sodium channel α-subunit, whereas two other sodium channel activators, veratridine and brevetoxin-2, were without effect. The ATX potency at rNav1.2, rNav1.4 and rNav1.5 did not differ significantly. Similarly, there were no significant differences in the efficacy for ATX-induced sodium influx between rNav1.2, rNav1.4 and rNav1.5 α-subunits. ATX also produced robust Ca2+ influx relative to other sodium channel activators in the calcium-permeable DEAA mutant of rNav1.4 α-subunit. Finally, we demonstrated that the 8-demethyl-8,9-dihydro-antillatoxin analog was less efficacious and less potent in stimulating sodium influx.ConclusionsATX displayed a unique efficacy with respect to stimulation of sodium influx in cells expressing rNav1.2, rNav1.4 and rNav1.5 α-subunits. The efficacy of ATX was distinctive inasmuch as it was not shared by activators of neurotoxin sites 2 and 5 on VGSC α-subunits. Given the unique pharmacological properties of ATX interaction with sodium channel α-subunits, decoding the molecular determinants and mechanism of action of antillatoxin may provide further insight into sodium channel gating mechanisms.

【 授权许可】

Unknown   
© Cao et al; licensee BioMed Central Ltd. 2010. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.