Journal Article

Chemical and Genetic Engineering of Selective Ion Channel—Ligand Interactions

Magnus, Christopher J., Looger, Loren L., Sternson, Scott M., Atasoy, Deniz, Su, Helen H., Lee, Peter H.

2011

Overview

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.

• Publisher: American Association for the Advancement of Science,The American Association for the Advancement of Science
• Subject: alpha7 Nicotinic Acetylcholine Receptor / Animal behavior / Animals / Behavioral neuroscience / Benzamides / Benzamides - chemistry / Benzamides - metabolism / Benzamides - pharmacology / Biological and medical sciences / Brain / Brain - cytology / Brain - physiology / Bridged Bicyclo Compounds - chemistry / Bridged Bicyclo Compounds - metabolism / Bridged Bicyclo Compounds - pharmacology / Cell membranes. Ionic channels. Membrane pores / Cell structures and functions / Cellular biology / Chemical engineering / chemistry / Cholinergic receptors / Drug interactions / Engineering / Feeding Behavior / Female / functional properties / Fundamental and applied biological sciences. Psychology / Genetic engineering / Genetics / HEK293 Cells / Humans / Ion Channel Gating / Ion channels / Ions / Ligand-Gated Ion Channels - chemistry / Ligand-Gated Ion Channels - genetics / Ligand-Gated Ion Channels - metabolism / Ligands / mammals / Membrane Potentials / Mice / Mice, Inbred C57BL / Molecular and cellular biology / Mutagenesis / Neurons / Neurons - physiology / Organic Chemistry / Patch-Clamp Techniques / Pharmacology / Physiology / Protein Binding / Protein Engineering / Protein Structure, Tertiary / Quinuclidines - chemistry / Quinuclidines - metabolism / Quinuclidines - pharmacology / Receptors / Receptors, Glycine - genetics / Receptors, Glycine - metabolism / Receptors, Nicotinic - chemistry / Receptors, Nicotinic - genetics / Receptors, Nicotinic - metabolism / Receptors, Serotonin, 5-HT3 - genetics / Receptors, Serotonin, 5-HT3 - metabolism / Recombinant Fusion Proteins - chemistry / Recombinant Fusion Proteins - metabolism / Small Molecule Libraries / Stereoisomerism