Développement de la technologie des récepteurs couplés à un canal ionique pour des études structure-fonction des récepteurs couplés aux protéines G et du canal Kir6.2

Abstract : Ion Channel-Coupled Receptors (ICCRs) are artificial ion channels created by the fusion of a Gprotein-coupled receptor to a Kir6.2 channel. In this concept, the channel acts a direct reporter ofthe conformational changes of the GPCRs, allowing the detection by simple current recordingsof agonists and antagonists binding in concentration-dependent manner.The signal being directly correlated to the receptor activity, independently of G protein signallingpathways, we exploited this advantage to extend the field of applications of ICCRs during thisthesis. We developed 4 applications: 1) the functional characterization of the optimized GPCRsfor crystallization by insertion of the T4 phage lysozyme domain in the ICL3 loop; 2) thedetection of a cholesterol-dependence of the GPCRs; 3) the detection of the so-called "biasedligands" to simplify their screening; and 4) the functional mapping of the Kir6.2 channel gatesunder control of membrane proteins interaction with the N-terminus domain.
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Katarzyna Niescierowicz. Développement de la technologie des récepteurs couplés à un canal ionique pour des études structure-fonction des récepteurs couplés aux protéines G et du canal Kir6.2. Sciences agricoles. Université de Grenoble, 2013. Français. ⟨NNT : 2013GRENV056⟩. ⟨tel-01067669⟩

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