Inhibition of potassium channel TREK1 by S6 kinases and cholesterol: a mechanism for aberrant neuronal excitability in mTORopathies – TOR-TREKking

The mammalian Target Of Rapamycin (mTOR) kinase is a master regulator of cell growth present in every eukaryotic cell, from unicellular organisms to humans. Genetic diseases, such as Tuberous Sclerosis Complex (TSC), leading to the up-regulation of mTOR activity predispose to altered cortical development, now classified as mTORopathies, which are associated with epilepsy as well as intellectual disability and autism. Our preliminary data identified one mTOR substrate, S6 kinases 1 (S6K1), as an essential factor for cortical malformations and seizures in a mouse model of TSC. In collaboration between the three partner teams, by phospho-proteomics and electrophysiological studies, we observed that S6K1 phosphorylates and inhibits the K+ channel TREK-1. Since TREK-1 influences neuronal excitability, we hypothesized that its down-regulation by S6K1-mediated phosphorylation may contribute to epileptic seizures in Tuberous Sclerosis. This model will be tested by original pharmacological, nutritional, biophysical and genetic approaches. Our project combines expertise in mTOR signaling and animal models of genetic diseases (partner 1), as well as skills in electrophysiology of K+ channels (partner 2) et epileptogenesis (partner 3), with the aim of exploring TREK1 contribution as a novel therapeutic target in epilepsy associated with mTORopathies.