期刊
BRITISH JOURNAL OF PHARMACOLOGY
卷 178, 期 5, 页码 1200-1217出版社
WILEY
DOI: 10.1111/bph.15365
关键词
arrhythmias; binding sites; epilepsy; local anaesthetics; pain; riluzole; sodium channels
资金
- Hungarian Brain Research Program [KTIA-NAP-13-2-2014-002]
- Hungary's Economic Development and Innovation Operative Programme [GINOP2.3.2-15-2016-00051]
- NKFIH [K127961]
- Semmelweis Science and Innovation Fund
The research found that riluzole mainly acts on Nav1.4 sodium channels by non-blocking modulation, selectively inhibiting pathological activity. Riluzole is identified as the prototype of a new class of sodium channel inhibitors, expected to selectively prevent hyperexcitability with minimal impact on normal cell activity.
Background and Purpose: Sodium channel inhibitors can be used to treat hyperexcitability-related diseases, including epilepsies, pain syndromes, neuromuscular disorders and cardiac arrhythmias. The applicability of these drugs is limited by their nonspecific effect on physiological function. They act mainly by sodium channel block and in addition by modulation of channel kinetics. While channel block inhibits healthy and pathological tissue equally, modulation can preferentially inhibit pathological activity. An ideal drug designed to target the sodium channels of pathological tissue would act predominantly by modulation. Thus far, no such drug has been described. Experimental Approach: Patch-clamp experiments with ultra-fast solution exchange and photolabeling-coupled electrophysiology were applied to describe the unique mechanism of riluzole on Nav1.4 sodium channels. In silico docking experiments were used to study the molecular details of binding. Key Results: We present evidence that riluzole acts predominantly by non-blocking modulation. We propose that, being a relatively small molecule, riluzole is able to stay bound to the binding site, but nonetheless stay off the conduction pathway, by residing in one of the fenestrations. We demonstrate how this mechanism can be recognized. Conclusions and Implications: Our results identify riluzole as the prototype of this new class of sodium channel inhibitors. Drugs of this class are expected to selectively prevent hyperexcitability, while having minimal effect on cells firing at a normal rate from a normal resting potential.
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