two-year post-doctoral position 2017-2018 (dead line for application october 15, 2016)
Title: Study of the in vivo functional consequences of the TWIK1 K+ channel selectivity
K+ channels play a key role in regulating cellular excitability. It was thought that the strong K+-selectivity of these channels was static, only altered by genetic mutations in their selectivity filter, which cause severe disorders. Recently, we have challenged this dogma by showing that selectivity of K+ channels can also exhibit dynamic changes in physiological conditions. Depending on its recycling rate or other stimuli not yet identified, the two pore domain K+ channel (K2P) TWIK1 can shift from a highly K+-selective state and thus with an repolarizing inhibitory role to a Na+-permeable channel, with a depolarizing excitatory role. This raises a number of questions, particularly on the impact of this TWIK1 property on cellular excitability and on whole organ functions. To address these questions, we are developing Knockin mouse models expressing mutated forms of TWIK1, locked either in the K+-selective state or in the cationic state.
The postdoctoral fellow will use these animal models to investigate the consequences of the TWIK1 dynamic selectivity in several organs, particularly in kidney, pancreas and adrenal gland in which TWIK1 is abundantly expressed.
The renal function of the two KI mouse models and also on a KO model will be evaluated under different diets using metabolic cages and by clearance experiments in anesthetized animals. The pancreatic function will be assessed by classical intraperitoneal glucose tolerance tests. Insulin secretion will be also measured from isolated perifused Langerhans islets and electrophysiological recording and Fura-2-Ca2+ measurements will be performed on isolated ß-cells to analyze the contribution of wild type or modified TWIK1 channels to the membrane voltage and cytosolic Ca2+ activity. Exploration of the adrenal function in the TWIK1 mouse models will involve measurement of steroid hormones under basal feeding conditions and diets enriched or depleted in sodium/potassium and measurement of arterial pressure. Calcium imaging on adrenal cells will be used as a method to indirectly assess zona glomerulosa cells membrane potential in those animals.
 Chatelain FC, Bichet D, Douguet D, Feliciangeli S, Bendahhou S, Reichold M, Warth R, Barhanin J and Lesage F (2012). TWIK1, a unique background channel with variable ion selectivity. Proceedings of the National Academy of Sciences of the United States of America, 109: 5499-504
The candidate should hold a PhD in physiology, pharmacology or related disciplines. She/he should be skilled in in vivo animal experimentation techniques as well as in cellular and molecular biology techniques. Practice or knowledge of imaging techniques would be appreciated.
Candidates should send a curriculum vitae with publication list, a short summary of research achievements, and the names and email addresses of at least two references to email@example.com