sodium channel 3

sodium channel 3 - Tarantula Huwentoxin-IV Inhibits...

Info iconThis preview shows pages 1–2. Sign up to view the full content.

View Full Document Right Arrow Icon

Info iconThis preview has intentionally blurred sections. Sign up to view the full version.

View Full DocumentRight Arrow Icon
This is the end of the preview. Sign up to access the rest of the document.

Unformatted text preview: Tarantula Huwentoxin-IV Inhibits Neuronal Sodium Channels by Binding to Receptor Site 4 and Trapping the Domain II Voltage Sensor in the Closed Configuration * S Received for publication, October 11, 2007, and in revised form, June 11, 2008 Published, JBC Papers in Press, July 14, 2008, DOI 10.1074/jbc.M708447200 Yucheng Xiao , Jon-Paul Bingham , Weiguo Zhu , Edward Moczydlowski , Songping Liang 1 , and Theodore R. Cummins 2 From the Department of Pharmacology and Toxicology, Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, Indiana 46202, Department of Molecular Biosciences and Bioengineering, University of Hawaii, Honolulu, Hawaii 96822, Department of Biology, Clarkson University, Potsdam, New York 13699, and Life Sciences College, Hunan Normal University, Changsha, Hunan 410081, China Peptide toxins with high affinity, divergent pharmacological functions, and isoform-specific selectivity are powerful tools for investigating the structure-function relationships of voltage- gated sodium channels (VGSCs). Although a number of inter- esting inhibitors have been reported from tarantula venoms, lit- tle is known about the mechanism for their interaction with VGSCs.Weshowthathuwentoxin-IV(HWTX-IV),a35-residue peptide from tarantula Ornithoctonus huwena venom, preferen- tially inhibits neuronal VGSC subtypes rNav1.2, rNav1.3, and hNav1.7 compared with muscle subtypes rNav1.4 and hNav1.5. Of the five VGSCs examined, hNav1.7 was most sensitive to HWTX-IV (IC 50 26 n M ). Following application of 1 M HWTX-IV, hNav1.7 currents could only be elicited with extreme depolarizations ( > 100 mV). Recovery of hNav1.7 channels from HWTX-IV inhibition could be induced by extreme depolarizations or moderate depolarizations lasting several minutes. Site-directed mutagenesis analysis indicated that the toxin docked at neurotoxin receptor site 4 located at the extracellular S3-S4 linker of domain II. Mutations E818Q and D816N in hNav1.7 decreased toxin affinity for hNav1.7 by 300-fold, whereas the reverse mutations in rNav1.4 (N655D/ Q657E) and the corresponding mutations in hNav1.5 (R812D/ S814E) greatly increased the sensitivity of the muscle VGSCs to HWTX-IV. Our data identify a novel mechanism for sodium channel inhibition by tarantula toxins involving binding to neu- rotoxinreceptorsite4.Incontrasttoscorpion-toxinsthattrap the IIS4 voltage sensor in an outward configuration, we propose that HWTX-IV traps the voltage sensor of domain II in the inward, closed configuration. Voltage-gated sodium channels (VGSCs) 3 are important transmembrane proteins expressed in most excitable tissues. The opening of the pore-forming subunit is responsible for the rapid depolarizing phase of action potentials. Nine dis- tinct VGSC subunit subtypes (Nav1.11.9) have been cloned from mammals (1, 2). The subunits share over 75% sequence similarity with each other and often exhibit similar functional properties. Because of these similarities, biologi-functional properties....
View Full Document

Page1 / 14

sodium channel 3 - Tarantula Huwentoxin-IV Inhibits...

This preview shows document pages 1 - 2. Sign up to view the full document.

View Full Document Right Arrow Icon
Ask a homework question - tutors are online