Publication Type Academic Article
Authors Gutzeit V, Acosta-Ruiz A, Munguba H, Häfner S, Landra-Willm A, Mathes B, Mony J, Yarotski D, Börjesson K, Liston C, Sandoz G, Levitz J, Broichhagen J
Journal Cell Chem Biol
Volume 28
Issue 11
Pagination 1648-1663.e16
Date Published 03/17/2021
ISSN 2451-9448
Keywords Azo Compounds, Potassium Channels, Receptors, Metabotropic Glutamate
Abstract Despite the power of photopharmacology for interrogating signaling proteins, many photopharmacological systems are limited by their efficiency, speed, or spectral properties. Here, we screen a library of azobenzene photoswitches and identify a urea-substituted "azobenzene-400" core that offers bistable switching between cis and trans with improved kinetics, light sensitivity, and a red-shift. We then focus on the metabotropic glutamate receptors (mGluRs), neuromodulatory receptors that are major pharmacological targets. Synthesis of "BGAG12,400," a photoswitchable orthogonal, remotely tethered ligand (PORTL), enables highly efficient, rapid optical agonism following conjugation to SNAP-tagged mGluR2 and permits robust optical control of mGluR1 and mGluR5 signaling. We then produce fluorophore-conjugated branched PORTLs to enable dual imaging and manipulation of mGluRs and highlight their power in ex vivo slice and in vivo behavioral experiments in the mouse prefrontal cortex. Finally, we demonstrate the generalizability of our strategy by developing an improved soluble, photoswitchable pore blocker for potassium channels.
DOI 10.1016/j.chembiol.2021.02.020
PubMed ID 33735619
PubMed Central ID PMC8435545
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