Mechanism-guided identification of antidepressant G protein-coupled receptor drug targets.
| Publication Type | Academic Article |
| Authors | Munguba H, Arefin A, Hasegawa R, Posa L, Romano G, Peddada T, Donatelle A, Singh A, Gutzeit V, Vijay A, Vaddi P, Kristt M, Shaver D, Hoque S, Broichhagen J, Stujenske J, Lee F, O'Brien E, Levitz J, Liston C |
| Journal | Cell |
| Date Published | 04/23/2026 |
| ISSN | 1097-4172 |
| Abstract | Depression is driven by dysfunction in discrete neural circuits, but a deeper understanding of the underlying molecular and synaptic mechanisms is needed to guide the development of therapeutics. Here, we decipher the mechanisms of action of the fast-acting antidepressant ketamine to enable the identification of G protein-coupled receptor (GPCR) antidepressant targets. We find that the behavioral effects of ketamine rely on mu-opioid receptors (MORs), which are enriched in somatostatin-expressing interneurons (Sst+ INs) in the medial prefrontal cortex (mPFC). Chronic stress drives presynaptic hypertrophy of mPFC Sst+ INs and excessive inhibition of pyramidal neurons, which is rescued by ketamine. Motivated by these findings, we use RNA sequencing to identify mPFC Sst+ IN-enriched GPCRs and validate the antidepressant potential of promising targets. Synergistic targeting of multiple GPCRs enables potent antidepressant-like responses with reduced side effects. Together, these findings reveal a general approach to identifying therapeutic GPCR targets for brain disorders. |
| DOI | 10.1016/j.cell.2026.04.006 |
| PubMed ID | 42030928 |