• Nanion Technologies: Smart Tools for Ion Channel Research

    Nanion Technologies: Smart Tools for Ion Channel Research

  • SyncroPatch 384i: HTS Automated Patch Clamp

    SyncroPatch 384i: HTS Automated Patch Clamp

  • SURFE²R 96SE: Label-free HTS Transporter Screening

    SURFE²R 96SE: Label-free HTS Transporter Screening

  • Dynamic Clamp: Patchliner

    Dynamic Clamp: Patchliner

  • Bilayer recordings: Orbit product family

    Bilayer recordings: Orbit product family

  • CardioExcyte 96 SOL: Pacing Cardiomyocytes with Light

    CardioExcyte 96 SOL: Pacing Cardiomyocytes with Light

Our Product Portfolio

SyncroPatch 384i

SyncroPatch 384i

Patchliner

Patchliner

Port-a-Patch

Port-a-Patch

Port-a-Patch mini

Port-a-Patch mini

CardioExcyte 96

CardioExcyte 96

FLEXcyte 96

FLEXcyte 96

SURFE²R 96SE

SURFE²R 96SE

SURFE²R N1

SURFE²R N1

Orbit 16

Orbit 16

Orbit Mini

Orbit Mini

Vesicle Prep Pro

Vesicle Prep Pro

2020 - Mechanism of non-blocking inhibition of sodium channels revealed by conformation-selective photolabeling

icon pap   Port-a-Patch pre-publication in BioRxiv (2020)

Authors:
Földi M.C., Pesti K., Zboray K., Hegedűs T., Málnási-Csizmadia A., Lukács P., Mike A.

Journal:
BioRxiv (2020) doi: 10.1101/2020.05.05.078071


Abstract:

Sodium channel inhibitor drugs can exert their effect by either blocking, or modulating the channel. The extent of modulation versus channel block is crucial regarding the therapeutic potential of drug candidates. Modulation can be selective for pathological hyperactivity, while channel block affects vital physiological function as much as pathological activity. Previous results indicated that riluzole, a drug with neuroprotective and antiepileptic effects, may have a unique mechanism of action, where modulation is predominant, and channel block is negligible. We studied the effects of riluzole on rNaV1.4 channels expressed in HEK cells. We observed that inhibition by riluzole disappeared and reappeared at a rate that could not be explained by association/dissociation dynamics. In order to verify the mechanism of non-blocking modulation, we synchronized photolabeling with the voltage clamp protocol of patch-clamp experiments. Using this method, we could bind a photoreactive riluzole analog covalently to specific conformations of the channel. Photolabeling was ineffective at resting conformation, but effective at inactivated conformation, as judged from persisting modulated gating after removal of unbound photoactive drug from the solution. Mutation of the key residue of the local anesthetic binding site (F1579A) did not fully prevent ligand binding and inhibition, however, it eliminated most of the modulation caused by ligand binding. Our results indicate that riluzole binds with highest affinity to the local anesthetic binding site, which transmits inhibition by the unique non-blocking modulation mechanism. Our results also suggest the existence of one or more additional binding sites, with lower affinity, and different inhibition mechanism.


Download here

Back to Overview

Nanion Corporate Blog

We use cookies on our website. Some of them are essential for the operation of the site, while others help us to improve this site and the user experience (tracking cookies). You can decide for yourself whether you want to allow cookies or not. Please note that if you reject them, you may not be able to use all the functionalities of the site.