Publication Type Academic Article
Authors Acosta-Ruiz A, Gutzeit V, Skelly M, Meadows S, Lee J, Parekh P, Orr A, Liston C, Pleil K, Broichhagen J, Levitz J
Journal Neuron
Volume 105
Issue 3
Pagination 446-463.e13
Date Published 11/26/2019
ISSN 1097-4199
Keywords Optogenetics, Photosensitizing Agents, Receptors, G-Protein-Coupled
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 Gi/o-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 Gq-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.
DOI 10.1016/j.neuron.2019.10.036
PubMed ID 31784287
PubMed Central ID PMC7216301
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