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Neuron. 2019 Nov 14. pii: S0896-6273(19)30931-6. doi: 10.1016/j.neuron.2019.10.036. [Epub ahead of print]

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

Author information

1
Biochemistry, Cell and Molecular Biology Graduate Program, Weill Cornell Medicine, New York, NY 10065, USA.
2
Neuroscience Graduate Program, Weill Cornell Medicine, New York, NY 10065, USA.
3
Department of Pharmacology, Weill Cornell Medicine, New York, NY 10065, USA.
4
Department of Biochemistry, Weill Cornell Medicine, New York, NY 10065, USA.
5
Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY 10065, USA.
6
Neuroscience Graduate Program, Weill Cornell Medicine, New York, NY 10065, USA; Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY 10065, USA; Appel Alzheimer's Disease Research Institute, Weill Cornell Medicine, New York, NY 10065, USA.
7
Neuroscience Graduate Program, Weill Cornell Medicine, New York, NY 10065, USA; Department of Pharmacology, Weill Cornell Medicine, New York, NY 10065, USA.
8
Department of Chemical Biology, Max Planck Institute for Medical Research, Jahnstr. 29, 69120 Heidelberg, Germany. Electronic address: johannes.broichhagen@mr.mpg.de.
9
Biochemistry, Cell and Molecular Biology Graduate Program, Weill Cornell Medicine, New York, NY 10065, USA; Department of Biochemistry, Weill Cornell Medicine, New York, NY 10065, USA; Tri-Institutional PhD Program in Chemical Biology, New York, NY 10065, USA. Electronic address: jtl2003@med.cornell.edu.

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.

KEYWORDS:

G protein-coupled receptor; astrocyte; calcium signaling; metabotropic glutamate receptor; neuromodulation; optogenetics; photopharmacology; prefrontal cortex; psychosis; working memory

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