Recommend Channels to your librarian for 2008. Download form here.
Sign up for Table of Contents Alerts.
Email this page
Print this page
Research Papers
µO-Conotoxins Inhibit NaV Channels by Interfering with their Voltage Sensors in Domain-2
Enrico Leipold, Herbert DeBie, Stefan Zorn, Borges Adolfo, Baldomero M Olivera, Heinrich Terlau and Stefan H Heinemann
volume 1 | issue 4
July/AugustPages: 253 - 262
We now provide open access to journal articles published online for one year or more. This article may be downloaded at the following link:
Download PDF If the document does not open, please right-click on the link (control-click on a Macintosh) and select the option to save the file to disk.
The µO-conotoxins MrVIA and MrVIB are 31-residue peptides from Conus marmoreus, belonging to the O-superfamily of conotoxins with three disulfide bridges. They have attracted attention because they are inhibitors of tetrodotoxin-insensitive voltage-gated sodium channels (NaV1.8) and could therefore serve as lead structure for novel analgesics. The aim of this study was to elucidate the molecular mechanism by which µO-conotoxins affect NaV channels. Rat NaV1.4 channels and mutants thereof were expressed in mammalian cells and were assayed with the whole-cell patch-clamp method. Unlike for the M-superfamily µ-conotoxin GIIIA from Conus geographus, channel block by MrVIA was strongly diminished after activating the NaV channels by depolarizing voltage steps. Searching for the source of this voltage dependence, the gating charges in all four voltage sensors were reduced by site-directed mutagenesis showing that alterations of the voltage sensor in domain-2 have the strongest impact on MrVIA action. These results, together with previous findings that the effect of MrVIA depends on the structure of the pore-loop in domain-3, suggest a functional similarity with scorpion β-toxins. In fact, MrVIA functionally competed with the scorpion β-toxin Ts1 from Tityus serrulatus, while it did not show competition with µ-GIIIA. Ts1 and µ-GIIIA did not compete either. Thus, similar to scorpion β-toxins, µO-conotoxins are voltage-sensor toxins targeting receptor site-4 on NaV channels. They "block" Na+ flow most likely by hindering the voltage sensor in domain-2 from activating and, hence, the channel from opening.
Authors
Enrico Leipold
Friedrich Schiller University Jena
Herbert DeBie
Friedrich Schiller University Jena
Stefan Zorn
Friedrich Schiller University Jena
Borges Adolfo
Universidad Central de Venezuela
Baldomero M Olivera
University of Utah
Heinrich Terlau
University of Luebeck
Stefan H Heinemann
Friedrich Schiller University Jena
We now provide open access to journal articles published online for one year or more. This article may be downloaded at the following link:
Download PDF If the document does not open, please right-click on the link (control-click on a Macintosh) and select the option to save the file to disk.