Molecular studies of ATP-sensitive potassium channels : gating, pathology, and optogenetics Gina Catalina Reyes-Mejia To cite this version: Gina Catalina Reyes-Mejia. Molecular studies of ATP-sensitive potassium channels : gating, pathol- ogy, and optogenetics. Biomolecules [q-bio.BM]. Université Grenoble Alpes, 2016. English. NNT : 2016GREAV012. tel-01497530 HAL Id: tel-01497530 https://tel.archives-ouvertes.fr/tel-01497530 Submitted on 28 Mar 2017 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. THÈSE Pour obtenir le grade de DOCTEUR DE LA COMMUNAUTE UNIVERSITE GRENOBLE ALPES Spécialité : Biologie Structurale et Nanobiologie Arrêté ministériel : 7 août 2006 Présentée par Gina Catalina REYES MEJIA Thèse dirigée par Dr. Michel VIVAUDOU préparée au sein du l’institut de Biologie Structurale dans l'École Doctorale Chimie et Science du Vivant Etudes moléculaires du canal potassique sensible à l'ATP:"gating", pathologie et optogénétique Thèse soutenue publiquement le 23 Septembre 2016 devant le jury composé de : Pr. Franck FIESCHI Président Dr. Thomas GRUTTER Rapporteur Dr. Gildas LOUSSOUARN Rapporteur Dr. Guillaume SANDOZ Examinateur Dr. Michel VIVAUDOU Directeur de thèse Université de Grenoble École Doctorale Chimie et Science du Vivant Thèse pour obtenir le grade de DOCTEUR EN SCIENCES DE L’UNIVERSITÉ DE GRENOBLE Specialité: Biologie Structurale et Nanobiologie Presented and defended in public by Gina Catalina REYES MEJIA On September 23th 2016 Molecular studies of ATP-sensitive potassium channels: Gating, pathology, and optogenetics Thesis director: Dr. Michel VIVAUDOU Jury: President: Pr. Franck FIESCHI Reviewer: Dr. Thomas GRUTTER Reviewer: Dr. Gildas LOUSSOUARN Examiner: Dr. Guillaume SANDOZ List of Abbreviations ABC ................................................................................................. ATP-Binding Cassette ADP ............................................................................................... Adenosine diphosphate ATP ............................................................................................... Adenosine triphosphate BR .......................................................................................................... Bacteriorhodopsin CFTR........................................ Cystic Fibrosis Transmembrane Conductance Regulator ChR ........................................................................................................ Channelrhodopsin CL................................................................................................................... Caged ligand COPI ..............................................................................................Coat Protein Complex I CS ............................................................................................................ Cantù Syndrome CTD .................................................................................................... Cytoplasmic domain ED ............................................................................................... Aspartate and Glutamate ER ................................................................................................. Endoplasmic Reticulum GPCR .................................................................................... G Protein-Coupled Receptor HR ................................................................................................................ Halorhodopsin ICCR .................................................................................Ion Channel-Coupled Receptor iGluR ....................................................................................Ionotropic glutamate receptor Kir ..............................................................................................Inward rectifier K+ channel KCO ....................................................................................... Potassium Channel Opener Kv ....................................................................................... Voltage dependent K+ channel LC-CoA .............................................................................Long chain Co-Enzyme A ester MAQ ....................................................... Maleimide Azobenzene Quaternary Ammonium MEA-TMA .................................. Maleimide Ethylene Azobenzene Trimethyl Ammonium NBD.......................................................................................... Nucleotide-binding domain PCLs .................................................................................................. Photochromic ligand PHHI.............................................. Persistent Hyperinsulinemic Hypoglycemia of Infancy Pi ........................................................................................................................ Phosphate PIP2 ........................................................................ Phosphatidylinositol-4,5-bisphosphate Po .............................................................................................................. Open probability PTL......................................................................................Photoswitched tethered ligand SPARK ........................................ Photoisomerizable Azobenzene Regulated K+ channel SUR.................................................................................................. Sulfonylurea receptor TM ............................................................................................. Transmembrane segment TMD ............................................................................................ Transmembrane domain VFTM ........................................................................................ Venus Flytrap Mechanism YCF1 ........................................................................................... Yeast Cadmium Factor 1 Table de Contents Objectives ........................................................................................... 8 Introduction ........................................................................................ 9 1. Potassium channels ............................................................................................ 10 1.a. The inward rectifying potassium channels (Kir)............................................. 11 1.a.1. Inward rectification .................................................................................... 12 1.a.2. Kir channel structures ................................................................................ 13 2. ABC transporters ................................................................................................. 18 2.a. Transport mechanism .................................................................................... 21 3. ATP-sensitive potassium channels ................................................................... 22 3.a. KATP channel summary ................................................................................... 22 3.b. The sulfonylurea receptor .............................................................................. 25 3.b.1. Isoforms and localization............................................................................ 25 3.b.2. Structural organization............................................................................... 25 3.c. Kir6 channels.................................................................................................. 26 3.d. SUR/Kir6 assembly and functional coupling ................................................. 27 3.d.1. SUR/Kir6 association .................................................................................. 27 3.d.2. SUR/Kir6 functional coupling ...................................................................... 30 4. KATP channel mechanism and regulation ......................................................... 31 4.a. Physiological regulation of the KATP channel by SUR ................................... 31 4.a.1. Regulation by Mg-nucleotides, specifically Mg-ADP...................................... 31 4.a.2. Regulation by Zinc ...................................................................................... 32 4.a.3. Regulation by G-proteins ............................................................................ 32 4.b. Physiological regulation of the KATP channel by Kir6..................................... 33 4.b.1. Regulation by nucleotides .......................................................................... 33 4.b.2. Regulation by lipids .................................................................................... 34 4.c. KATP channel physiology and physiopathology .............................................. 35 4.c.1. KATP channels in the pancreas ...................................................................... 35 4.c.2. KATP channels in the central nervous system ................................................. 37 4.c.3. Muscle KATP channels .................................................................................. 37 4.d. KATP