A tentative model of sodium channels redefines direct and indirect involvement of residues in drug binding at the local anesthetic receptor

Abstract

Event Abstract Back to Event A tentative model of sodium channels redefines direct and indirect involvement of residues in drug binding at the local anesthetic receptor Arpad Mike1* and Peter Lukacs1 1 Institute of Experimental Medicine, Hungary Discovery of novel sodium channel inhibitor compounds is a much desired goal of current pharmaceutical research. Many potential drugs have been patented in the last few years for indications such as epilepsy, chronic pain, neuropathic pain, migraine headache, spasticity, tremor, ischemic neuronal damage, neurodegenerative diseases, bipolar disease, obsessive-compulsive disorder, etc. Effective drug development requires an in-depth knowledge of the target protein, especially its drug binding site. Despite the intricate details of knowledge accumulated thus far, some of the most fundamental questions – such as which exact residues constitute the binding site, how many binding sites are present, or which specific drugs bind to respective binding sites – are still largely unanswered. Residues involved in drug binding at the “local anesthetic receptor” of sodium channels are assumed to face the inner pore, where the drug is supposed to be located during block. However, in different laboratories different residues have been found to be important for drug binding, therefore in three of the four domains of the sodium channel, D1, D2 and D3, the orientation of S6 segments is controversial. We have reviewed the literature on the effects of mutagenesis on drug binding, and propose a model of sodium channels which is compatible with most experimental data, and which can be helpful for discriminating between direct and indirect effects of mutations of individual residues on apparent affinity. We propose that conserved asparagine residues in all four domains may be involved in voltage sensor – activation gate coupling. We discuss hypotheses about alternative binding sites, and compare the effect of mutations on the affinity of different drugs, in order to examine whether they bind to the same binding site. Conference: IBRO International Workshop 2010, Pécs, Hungary, 21 Jan - 23 Jan, 2010. Presentation Type: Poster Presentation Topic: Abstracts Citation: Mike A and Lukacs P (2010). A tentative model of sodium channels redefines direct and indirect involvement of residues in drug binding at the local anesthetic receptor. Front. Neurosci. Conference Abstract: IBRO International Workshop 2010. doi: 10.3389/conf.fnins.2010.10.00251 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 05 May 2010; Published Online: 05 May 2010. * Correspondence: Arpad Mike, Institute of Experimental Medicine, Budapest, Hungary, arpadmike1@gmail.com Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Arpad Mike Peter Lukacs Google Arpad Mike Peter Lukacs Google Scholar Arpad Mike Peter Lukacs PubMed Arpad Mike Peter Lukacs Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.