title: Chemical and genetic engineering of selective ion channel-ligand interactions.
abstract: Ionic flux mediates essential physiological and behavioral functions in defined cell populations. Cell type-specific activators of diverse ionic conductances are needed for probing these effects. We combined chemistry and protein engineering to enable the systematic creation of a toolbox of ligand-gated ion channels (LGICs) with orthogonal pharmacologic selectivity and divergent functional properties. The LGICs and their small-molecule effectors were able to activate a range of ionic conductances in genetically specified cell types. LGICs constructed for neuronal perturbation could be used to selectively manipulate neuron activity in mammalian brains in vivo. The diversity of ion channel tools accessible from this approach will be useful for examining the relationship between neuronal activity and animal behavior, as well as for cell biological and physiological applications requiring chemical control of ion conductance.
authors: Janelia Farm Research Campus, Howard Hughes Medical Institute, 19700 Helix Drive, Ashburn, VA 20147, USA.
authors: Christopher J
authors: CJ
authors: Magnus
authors: Peter H
authors: PH
authors: Lee
authors: Deniz
authors: D
authors: Atasoy
authors: Helen H
authors: HH
authors: Su
authors: Loren L
authors: LL
authors: Looger
authors: Scott M
authors: SM
authors: Sternson
mesh_terms: D000818:Animals; D001549:Benzamides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D001921:Brain / Q000166:cytology / Q000502:physiology; D001643:Bridged Bicyclo Compounds / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D005247:Feeding Behavior; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D015640:Ion Channel Gating; D058446:Ligand-Gated Ion Channels / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D008024:Ligands; D008564:Membrane Potentials; D051379:Mice; D008810:Mice, Inbred C57BL; D016296:Mutagenesis; D009474:Neurons / Q000502:physiology*; D018408:Patch-Clamp Techniques; D011485:Protein Binding; D015202:Protein Engineering; D017434:Protein Structure, Tertiary; D011812:Quinuclidines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D018009:Receptors, Glycine / Q000235:genetics / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D044406:Receptors, Serotonin, 5-HT3 / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000378:metabolism; D054852:Small Molecule Libraries; D013237:Stereoisomerism; D064569:alpha7 Nicotinic Acetylcholine Receptor
chemical_list: D001549:Benzamides; D001643:Bridged Bicyclo Compounds; C579167:Chrna7 protein, human; C579166:Chrna7 protein, mouse; D058446:Ligand-Gated Ion Channels; D008024:Ligands; C498513:PNU-282987; D011812:Quinuclidines; D018009:Receptors, Glycine; D011978:Receptors, Nicotinic; D044406:Receptors, Serotonin, 5-HT3; D011993:Recombinant Fusion Proteins; D054852:Small Molecule Libraries; D064569:alpha7 Nicotinic Acetylcholine Receptor; C060432:3-aminoquinuclidine