title: Remote and reversible inhibition of neurons and circuits by small molecule induced potassium channel stabilization.
abstract: Manipulating the function of neurons and circuits that translate electrical and chemical signals into behavior represents a major challenges in neuroscience. In addition to optogenetic methods using light-activatable channels, pharmacogenetic methods with ligand induced modulation of cell signaling and excitability have been developed. However, they are largely based on ectopic expression of exogenous or chimera proteins. Now, we describe the remote and reversible expression of a Kir2.1 type potassium channel using the chemogenetic technique of small molecule induced protein stabilization. Based on shield1-mediated shedding of a destabilizing domain fused to a protein of interest and inhibition of protein degradation, this principle has been adopted for biomedicine, but not in neuroscience so far. Here, we apply this chemogenetic approach in brain research for the first time in order to control a potassium channel in a remote and reversible manner. We could show that shield1-mediated ectopic Kir2.1 stabilization induces neuronal silencing in vitro and in vivo in the mouse brain. We also validated this novel pharmacogenetic method in different neurobehavioral paradigms.The DD-Kir2.1 may complement the existing portfolio of pharmaco- and optogenetic techniques for specific neuron manipulation, but it may also provide an example for future applications of this principle in neuroscience research.
authors.affiliation: Department of Internal Medicine II, Klinikum rechts der Isar, Technical University of Munich, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Auffenberg
authors.affiliation: Department of Internal Medicine II, Klinikum rechts der Isar, Technical University of Munich, Germany.
authors.forename: Angela
authors.initials: A
authors.lastname: Jurik
authors.affiliation: Institute of Anesthesiology, Technical University of Munich, Germany.
authors.forename: Corinna
authors.initials: C
authors.lastname: Mattusch
authors.affiliation: Max Planck Institute of Psychiatry, Department of Stress Physiology and Neurogenetics, Munich, Germany.
authors.forename: Rainer
authors.initials: R
authors.lastname: Stoffel
authors.affiliation: Max Planck Institute of Psychiatry, Department of Stress Physiology and Neurogenetics, Munich, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Genewsky
authors.affiliation: Max Planck Institute of Psychiatry, Department of Stress Physiology and Neurogenetics, Munich, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Namendorf
authors.affiliation: Department of Internal Medicine II, Klinikum rechts der Isar, Technical University of Munich, Germany.
authors.forename: Roland M
authors.initials: RM
authors.lastname: Schmid
authors.affiliation: Institute of Anesthesiology, Technical University of Munich, Germany.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Rammes
authors.affiliation: Center for Integrated Protein Science Munich (CIPSM) and Department of Pharmacy - Center for Drug Research, Ludwig-Maximilians-University of Munich, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Biel
authors.affiliation: Max Planck Institute of Psychiatry, Department of Stress Physiology and Neurogenetics, Munich, Germany.
authors.forename: Manfred
authors.initials: M
authors.lastname: Uhr
authors.affiliation: Institute of Pharmacology, Technical University of Munich, Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Moosmang
authors.affiliation: Center for Integrated Protein Science Munich (CIPSM) and Department of Pharmacy - Center for Drug Research, Ludwig-Maximilians-University of Munich, Germany.
authors.forename: Stylianos
authors.initials: S
authors.lastname: Michalakis
authors.affiliation: Max Planck Institute of Psychiatry, Department of Stress Physiology and Neurogenetics, Munich, Germany.
authors.forename: Carsten T
authors.initials: CT
authors.lastname: Wotjak
authors.affiliation: Department of Internal Medicine II, Klinikum rechts der Isar, Technical University of Munich, Germany.
authors.forename: Christoph K
authors.initials: CK
authors.lastname: Thoeringer
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002460:Cell Line; D006801:Humans; D008568:Memory / Q000187:drug effects; D051379:Mice; D009025:Morpholines / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects* / Q000502:physiology*; D015221:Potassium Channels / Q000235:genetics / Q000378:metabolism*; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics / Q000378:metabolism; D054730:Protein Interaction Domains and Motifs / Q000235:genetics; D055550:Protein Stability / Q000187:drug effects; D022061:Tacrolimus Binding Protein 1A / Q000235:genetics / Q000378:metabolism
chemical_list: C489461:Kir2.1 channel; D009025:Morpholines; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; C540198:Shield-1 compound; D022061:Tacrolimus Binding Protein 1A