KELEGANS – Genetics and cell biology of K2P channels

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. Despite the fundamental functions of these channels, comparatively little is known about the specific factors and cellular processes that control K2P function in vivo.

The goal of this project is to use comprehensive genetic and genomic screening strategies in the model nematode C. elegans to identify conserved factors and cellular processes that control the biology of two-pore domain potassium channels. We will take advantage of recent progress in deep sequencing technologies to rapidly clone genetic mutations isolated in forward genetic screens. We will carry out whole-genome RNAi and yeast two-hybrid screens, because they may give us access to additional classes of K2P regulators. Next, we will use a wide range of experimental approaches including genetics, genome engineering, fluorescence imaging, in vivo and ex vivo electrophysiology, to functionally characterize candidate regulators. This way, we aim to produce a complete picture of the role of novel and conserved factor in the regulation of K2P channel function.

In summary, we will
1/ conduct large-scale genetic screens to identify novel genes that regulate K2P channels.
2/ functionally characterize conserved regulators of K2P channels in C. elegans and heterologous systems.
3/ develop innovative strategies to study conserved K2P channels in C. elegans.

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