Genetics and cell biology of K2P channels (Kelegans)
Genetics and cell biology of K2P channels
Start date: Oct 1, 2013,
End date: Sep 30, 2018
Two-pore domain potassium channels (K2P) maintain the resting membrane potential of animal cells and therefore play a central role in the control of cellular excitability. In the vertebrate nervous system, various neuromodulators promote K2P closure, which depolarizes neurons, increases neuronal excitability and ultimately affects action potential firing. Knockout studies have revealed important roles of K2Ps in physiopathological processes tied to cellular excitability. K2Ps are major targets of volatile anaesthetics. Analysis of task1/3 knockouts established a direct role of these channels in anaesthetics-induced immobilization and sedation. trek1 knockout mice are hypersensitive to kainate-induced seizures and display depression-resistant phenotypes, similar to naive mice treated with selective serotonine reuptake inhibitors. In sensory neurons, genetic ablation of trek1 or inhibition by noxious stimuli (heat, external acidosis) leads to increased neuronal activity and pain perception.Despite the fundamental functions of these channels, comparatively little is known about the cellular processes that control K2P function. I propose to use comprehensive and powerful genetic screening strategies in the nematode C. elegans to identify novel genes and conserved cellular processes that regulate the biology of K2Ps in a native context. I will decipher the precise functions of novel K2P regulators by using the full array of techniques available in C. elegans including genetics, live imaging, electrophysiology and state-of-the-art genome engineering and deep sequencing. This will provide new leads to understand the cellular pathways that control K2P function in other organisms.This work may have wide-ranging applications since K2Ps are increasingly implicated in a variety of physiopathological processes in the nervous system but also in cardiac muscle, endocrine and immune system. However, the precise molecular factors involved are mostly unknown.
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