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

Overview

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.

publication date

  • November 26, 2019

Research

keywords

  • Optogenetics
  • Photosensitizing Agents
  • Receptors, G-Protein-Coupled

Identity

PubMed Central ID

  • PMC7216301

Scopus Document Identifier

  • 85078681526

Digital Object Identifier (DOI)

  • 10.1016/j.neuron.2019.10.036

PubMed ID

  • 31784287

Additional Document Info

volume

  • 105

issue

  • 3