Abstract
Photoswitchable blockers of potassium channels can be used to optically control neuronal excitability and hold great promise for vision restoration. Here, we report a series of improved photoswitchable blockers that are furnished with a new pharmacophore based on the local anesthetic bupivacaine. These azobupivacaines (ABs) enable optical control over the delayed rectifier channel Kv2.1. and target the two-pore domain potassium channel TREK-1. For the first time, we have identified a compound that blocks conductance in the dark and potentiates it upon illumination. Using light as a trigger, ABs efficiently and reversibly silence action potential firing of hippocampal neurons in acute mouse brain slices.
Keywords:
Kv2.1; Photochromic ligand; TREK-1; channel blocker; local anesthetics; photopharmacology.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Action Potentials / drug effects*
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Animals
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Azo Compounds / chemical synthesis
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Azo Compounds / pharmacology*
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Bupivacaine / analogs & derivatives*
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HEK293 Cells
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Hippocampus / cytology
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Hippocampus / drug effects
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Hippocampus / metabolism
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Humans
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Light*
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Mice
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Neurons / drug effects*
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Neurons / metabolism
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Optical Phenomena
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Potassium Channel Blockers / chemical synthesis
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Potassium Channel Blockers / pharmacology*
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Potassium Channels, Tandem Pore Domain / antagonists & inhibitors
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Potassium Channels, Tandem Pore Domain / drug effects*
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Potassium Channels, Tandem Pore Domain / metabolism
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Shab Potassium Channels / antagonists & inhibitors
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Shab Potassium Channels / drug effects*
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Shab Potassium Channels / metabolism
Substances
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Azo Compounds
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Potassium Channel Blockers
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Potassium Channels, Tandem Pore Domain
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Shab Potassium Channels
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potassium channel protein TREK-1
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Bupivacaine