2. Academic Validation
  3. Mechanism-guided identification of antidepressant G protein-coupled receptor drug targets

Mechanism-guided identification of antidepressant G protein-coupled receptor drug targets

  • Cell. 2026 Apr 30;189(9):2612-2632.e24. doi: 10.1016/j.cell.2026.04.006.
Hermany Munguba 1,  Anisul Arefin 2,  Ryota Hasegawa 3,  Luca Posa 2,  Giovanna R Romano 2,  Teja N Peddada 4,  Alexander Donatelle 1,  Ashna Singh 1,  Vanessa A Gutzeit 2,  Akshara Vijay 2,  Prerana Vaddi 2,  Melanie Kristt 2,  Daniel Shaver 3,  Shanjida Hoque 2,  Johannes Broichhagen 5,  Joseph M Stujenske 6,  Francis S Lee 3,  Evan O'Brien 7,  Joshua Levitz 8,  Conor Liston 9
Affiliations

Affiliations

  • 1 Department of Biochemistry and Biophysics, Weill Cornell Medicine, New York, NY, USA; Department of Psychiatry, Weill Cornell Medicine, New York, NY, USA.
  • 2 Department of Biochemistry and Biophysics, Weill Cornell Medicine, New York, NY, USA.
  • 3 Department of Psychiatry, Weill Cornell Medicine, New York, NY, USA.
  • 4 Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA.
  • 5 Department of Chemical Biology, Forschungsinstitut für Molekulare Pharmakologie, Berlin, Germany.
  • 6 Department of Psychiatry, Weill Cornell Medicine, New York, NY, USA; Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA.
  • 7 Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA; Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • 8 Department of Biochemistry and Biophysics, Weill Cornell Medicine, New York, NY, USA; Department of Psychiatry, Weill Cornell Medicine, New York, NY, USA. Electronic address: [email protected].
  • 9 Department of Psychiatry, Weill Cornell Medicine, New York, NY, USA. Electronic address: [email protected].
PMID: 42030928 DOI: 10.1016/j.cell.2026.04.006
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.

Keywords

GPCR; antidepressant; ketamine; neuromodulation; opioid receptor; photopharmacology; prefrontal cortex; somatostatin interneuron; synaptic plasticity; two-photon imaging.

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