Structural basis for the rescue of hyperexcitable cells by the amyotrophic lateral sclerosis drug Riluzole.

ABSTRACT: Neuronal hyperexcitability is a key element of many neurodegenerative disorders including the motor neuron disease Amyotrophic Lateral Sclerosis (ALS), where it occurs associated with elevated late sodium current (I_NaL). I_NaL results from incomplete inactivation of voltage-gated sodium channels (VGSCs) after their opening and shapes physiological membrane excitability. However, dysfunctional increases can cause hyperexcitability-associated diseases. Here we reveal the atypical binding mechanism which explains how the neuroprotective ALS-treatment drug riluzole stabilises VGSCs in their inactivated state to cause the suppression of I_NaL that leads to reversed cellular overexcitability. Riluzole accumulates in the membrane and enters VGSCs through openings to

SUBMITTER: Hollingworth D 

PROVIDER: S-EPMC11438954 | biostudies-literature | 2024 Sep

REPOSITORIES: biostudies-literature