Psychedelic-inspired drug discovery using an engineered biosensor

Chunyang Dong, Calvin Ly, Lee E. Dunlap, Maxemiliano V. Vargas, Junqing Sun, In Wook Hwang, Arya Azinfar, Won Chan Oh, William C. Wetsel, David E. Olson, Lin Tian

Research output: Contribution to journalArticlepeer-review

Abstract

Ligands can induce G protein-coupled receptors (GPCRs) to adopt a myriad of conformations, many of which play critical roles in determining the activation of specific signaling cascades associated with distinct functional and behavioral consequences. For example, the 5-hydroxytryptamine 2A receptor (5-HT2AR) is the target of classic hallucinogens, atypical antipsychotics, and psychoplastogens. However, currently available methods are inadequate for directly assessing 5-HT2AR conformation both in vitro and in vivo. Here, we developed psychLight, a genetically encoded fluorescent sensor based on the 5-HT2AR structure. PsychLight detects behaviorally relevant serotonin release and correctly predicts the hallucinogenic behavioral effects of structurally similar 5-HT2AR ligands. We further used psychLight to identify a non-hallucinogenic psychedelic analog, which produced rapid-onset and long-lasting antidepressant-like effects after a single administration. The advent of psychLight will enable in vivo detection of serotonin dynamics, early identification of designer drugs of abuse, and the development of 5-HT2AR-dependent non-hallucinogenic therapeutics.

Original languageEnglish (US)
Pages (from-to)2779-2792.e18
JournalCell
Volume184
Issue number10
DOIs
StatePublished - May 13 2021

Keywords

  • depression
  • genetically encoded indicators
  • hallucinogen
  • psychedelic
  • serotonin
  • serotonin receptors

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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