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