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

Neuron. 2020 Feb 5;105(3):446-463.e13. doi: 10.1016/j.neuron.2019.10.036. Epub 2019 Nov 26.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • HEK293 Cells
  • Humans
  • Ligands
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Optogenetics / methods*
  • Photosensitizing Agents / chemistry
  • Photosensitizing Agents / metabolism*
  • Photosensitizing Agents / pharmacology
  • Receptors, G-Protein-Coupled / agonists*
  • Receptors, G-Protein-Coupled / metabolism*
  • Receptors, Metabotropic Glutamate / agonists
  • Receptors, Metabotropic Glutamate / metabolism


  • Ligands
  • Photosensitizing Agents
  • Receptors, G-Protein-Coupled
  • Receptors, Metabotropic Glutamate
  • metabotropic glutamate receptor 2