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  Branched photoswitchable tethered ligands enable ultra-efficient optical control and detection of G protein-coupled receptors in vivo

Acosta-Ruiz, A., Gutzeit, V. A., Skelly, M. J., Meadows, S., Lee, J., Parekh, P., et al. (2020). Branched photoswitchable tethered ligands enable ultra-efficient optical control and detection of G protein-coupled receptors in vivo. Neuron, 105, 1-18. doi:10.1016/j.neuron.2019.10.036.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0005-45A4-4 Version Permalink: http://hdl.handle.net/21.11116/0000-0005-45A5-3
Genre: Journal Article

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 Creators:
Acosta-Ruiz, Amanda, Author
Gutzeit, Vanessa A., Author
Skelly, Mary Jane, Author
Meadows, Samantha, Author
Lee, Joon, Author
Parekh, Puja, Author
Orr, Anna G., Author
Liston, Conor, Author
Pleil, Kristen E., Author
Broichhagen, Johannes1, Author              
Levitz, Joshua, Author
Affiliations:
1Chemical Biology, Max Planck Institute for Medical Research, Max Planck Society, ou_2364732              

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Free keywords: photopharmacology; optogenetics; neuromodulation; G protein-coupled receptor; metabotropic glutamate receptor; calcium signaling; astrocyte; prefrontal cortex; working memory; psychosis
 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 i/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 G q-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.

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Language(s): eng - English
 Dates: 2019-11-262019-11-262020-02-05
 Publication Status: Published in print
 Pages: 32
 Publishing info: -
 Table of Contents: -
 Rev. Method: Peer
 Identifiers: DOI: 10.1016/j.neuron.2019.10.036
 Degree: -

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Title: Neuron
Source Genre: Journal
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Publ. Info: Cambridge, Mass. : Cell Press
Pages: - Volume / Issue: 105 Sequence Number: - Start / End Page: 1 - 18 Identifier: ISSN: 0896-6273
CoNE: https://pure.mpg.de/cone/journals/resource/954925560565