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Branched Photoswitchable Tethered Ligands Enable Ultra-efficient Optical Control and Detection of G Protein-Coupled Receptors In Vivo.

TitleBranched Photoswitchable Tethered Ligands Enable Ultra-efficient Optical Control and Detection of G Protein-Coupled Receptors In Vivo.
Publication TypeJournal Article
Year of Publication2020
AuthorsAcosta-Ruiz A, Gutzeit VA, Skelly MJane, Meadows S, Lee J, Parekh P, Orr AG, Liston C, Pleil KE, Broichhagen J, Levitz J
JournalNeuron
Volume105
Issue3
Pagination446-463.e13
Date Published2020 02 05
ISSN1097-4199
KeywordsAnimals, Cells, Cultured, HEK293 Cells, Humans, Ligands, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Optogenetics, Photosensitizing Agents, Receptors, G-Protein-Coupled, Receptors, Metabotropic Glutamate
Abstract

The limitations of classical drugs have spurred the development of covalently tethered photoswitchable ligands to control neuromodulatory receptors. However, a major shortcoming of tethered photopharmacology is the inability to obtain optical control with an efficacy comparable with that of the native ligand. To overcome this, we developed a family of branched photoswitchable compounds to target metabotropic glutamate receptors (mGluRs). These compounds permit photo-agonism of G-coupled group II mGluRs with near-complete efficiency relative to glutamate when attached to receptors via a range of orthogonal, multiplexable modalities. Through a chimeric approach, branched ligands also allow efficient optical control of G-coupled mGluR5, which we use to probe the spatiotemporal properties of receptor-induced calcium oscillations. In addition, we report branched, photoswitch-fluorophore compounds for simultaneous receptor imaging and manipulation. Finally, we demonstrate this approach in vivo in mice, where photoactivation of SNAP-mGluR2 in the medial prefrontal cortex reversibly modulates working memory in normal and disease-associated states.

DOI10.1016/j.neuron.2019.10.036
Alternate JournalNeuron
PubMed ID31784287