RT Journal Article
SR Electronic
T1 Non-blocking modulation as the major mechanism of sodium channel inhibition by riluzole
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 228569
DO 10.1101/228569
A1 AK Szabo
A1 K Pesti
A1 P Lukacs
A1 MC Földi
A1 Z Gerevich
A1 B Sperlagh
A1 A Mike
YR 2017
UL http://biorxiv.org/content/early/2017/12/04/228569.abstract
AB Modulated- or guarded receptor hypothesis; Channel block or modulation; “Voltage-sensor block” or “lipophilic block” are some of the questions that arise when drug effects on sodium channels are investigated. Understanding the exact mechanism of action for individual drugs is essential, because it is one of the major factors that determine their therapeutic applicability.In this study we created a kinetic model of sodium channels, which can help us understand the modes of action for individual drugs in the context of these hypotheses. The model was constructed so that it could integrate the above hypotheses.In particular we aimed to understand the mode of action of riluzole, a neuroprotective drug with a peculiar state-dependent inhibition. In experiments the inhibition by 100μM riluzole was full within the first two milliseconds, but it was almost completely removed between 2 and 20 ms post-depolarization. This abrupt loss of inhibition could not be explained by dissociation, which was proceeding with a time constant of ~300 ms. We propose that for sodium channel inhibitors binding without blocking is possible, and riluzole predominantly inhibits by non-blocking modulation. We used lidocaine as a reference compound, and found that non-blocking modulation, although less prominent, also may play a role in its mechanism of inhibition. Non-blocking modulation may selectively inhibit cells with pathological activity patterns, therefore this property may be a good trait to investigate in the development of sodium channel inhibitor drugs.SUMMARY Although never actually proven, presence of sodium channel inhibitors at their binding site is assumed to prevent ion conduction. Authors provide evidence from experiments and kinetic simulations that bound riluzole permits conduction and exerts its inhibitory effect almost entirely by modulation.SCIsodium channel inhibitorMRHmodulated receptor hypothesisGRHguarded receptor hypothesisSSIsteady-state inactivation protocolRFIrecovery from inactivation3PTthree pulse trainR, C, O, F, AR, AC, AO, AF, BR, BC, BO, BFstates of the model:RrestingCclosed inactivatedOopenFinactivated (fast inactivated)AXany of the accessed states BX – any of the bound statesAFBallosteric factor stabilizing drug-bound fast inactivated stateAOBallosteric factor stabilizing drug-bound open stateGFA“guard factor”, accelerating access/egress to/from fast inactivated statesGOA“guard factor”, accelerating access/egress to/from open statesGFBg“guard factor for fast inactivation/recoveryBlAblocked fraction for accessed channelsBlBblocked fraction for bound channelsBlblocked fraction for accessed and bound channelsRILriluzoleLIDlidocaine