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Non-blocking modulation contributes to sodium channel inhibition by a covalently attached photoreactive riluzole analog

Lukács, Péter and Földi, M. C. and Valanszki, L. and Casanova, E. and Biri, Beáta and Nyitray, László and Málnási Csizmadia, András and Mike, Árpád (2018) Non-blocking modulation contributes to sodium channel inhibition by a covalently attached photoreactive riluzole analog. SCIENTIFIC REPORTS, 8. ISSN 2045-2322

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Abstract

Sodium channel inhibitor drugs decrease pathological hyperactivity in various diseases including pain syndromes, myotonia, arrhythmias, nerve injuries and epilepsies. Inhibiting pathological but not physiological activity, however, is a major challenge in drug development. Sodium channel inhibitors exert their effects by a dual action: they obstruct ion flow ("block"), and they alter the energetics of channel opening and closing ("modulation"). Ideal drugs would be modulators without blocking effect, because modulation is inherently activity-dependent, therefore selective for pathological hyperactivity. Can block and modulation be separated? It has been difficult to tell, because the effect of modulation is obscured by conformation-dependent association/dissociation of the drug. To eliminate dynamic association/dissociation, we used a photoreactive riluzole analog which could be covalently bound to the channel; and found, unexpectedly, that drug-bound channels could still conduct ions, although with modulated gating. The finding that non-blocking modulation is possible, may open a novel avenue for drug development because non-blocking modulators could be more specific in treating hyperactivity-linked diseases.

Item Type: Article
Uncontrolled Keywords: NEURONS; MECHANISMS; RECEPTORS; RECOMBINATION; CONFORMATIONS; Electrophysiology; lidocaine; DRUG DISCOVERY; LOCAL-ANESTHETICS; DEPENDENT BLOCK;
Subjects: R Medicine / orvostudomány > RC Internal medicine / belgyógyászat > RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry / idegkórtan, neurológia, pszichiátria
R Medicine / orvostudomány > RM Therapeutics. Pharmacology / terápia, gyógyszertan
SWORD Depositor: MTMT SWORD
Depositing User: MTMT SWORD
Date Deposited: 29 Dec 2018 13:52
Last Modified: 29 Dec 2018 13:52
URI: http://real.mtak.hu/id/eprint/88928

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