Potential for Improved Psychiatric Medication Efficacy with Serotonin Receptor 5-HT1A Found to Favor Certain Signaling Pathways

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In a recent study, researchers from the Icahn School of Medicine at Mount Sinai found that serotonin receptor 5-HT1A has inherent properties favoring certain cellular signaling pathways, regardless of the drug used to impact the receptor.¹ The study is the first of its kind to document such a pathway-favoring property and could provide insight for developing faster acting psychiatric medications.

Because the receptor signals through inhibitory G proteins, the investigators identified a potent partial agonist that selectively engages a G protein subtype via in vitro assays. Using cryo–electron microscopy, they investigated the differences in G protein engagement at 5-HT1A to ascertain structures of 5-HT1A bound to distinct ligands and G protein subtypes. They specifically leveraged the antipsychotic asenapine to help explore how 5-HT1A engages G protein pathways and how asenapine stimulates receptor activation. Still, different drugs can influence the level of strength at which the molecular pathways are activated. Phospholipids were also found to play an important role in influencing the activity of 5-HT1A.

“Our work provides a molecular map of how different drugs ‘push buttons’ on this receptor—activating or silencing specific pathways that influence brain function,” Audrey L. Warren, PhD, lead author and postdoctoral researcher at Columbia University, said in a press release.² “By understanding exactly how these drugs interact with the receptor, we can start to predict which approaches might lead to more effective or targeted treatments and which ones are unlikely to work. It’s a step toward designing next-generation therapies with greater precision and fewer side effects.”

Daniel Wacker, PhD, assistant professor of pharmacological sciences and neuroscience at the Icahn School of Medicine at Mount Sinai and senior author of the study, likened the 5-HT1A serotonin receptor to a control panel. “Our findings shed light on how that control panel operates—what switches it flips, how it fine-tunes signals, and where its limits lie. This deeper understanding could help us design better therapies for mental health conditions like depression, anxiety, and schizophrenia,” he said in a press statement.²

The deeper molecular knowledge resulting from these combined techniques may yield designs for faster and more effective treatments. “By understanding how [the receptor] functions at a molecular level, we have a clearer path to designing faster, more effective treatments, not just for depression, but also for conditions like psychosis and chronic pain. It’s a key piece of the puzzle,” Wacker said.² Wacker added that such research also may bring insight into why traditional antidepressants take longer periods of time before their effects are seen.

The researchers also noted the potential role of phospholipids as a co-factor in efficacy. “Our studies further implicate endogenous lipids in the activation of distinct signaling pathways at 5-HT1A—and possibly other GPCRs,” they reported, noting this is the first time a phospholipid has been observed acting like a “co-pilot” and steering the receptor’s activity.^1,2 “Although PtdIns4P [phosphatidylinositol-4-phosphate] is broadly distributed, lipid composition at the plasma membrane differs across tissues and cell types. Lipid distribution and its regulation may thus play a key role in the activity of 5-HT1A and potentially other receptors.” As such, the study authors look to further investigate the role of phospholipids.

References

1.Warren AL, Zilberg G, Abbassi A, et al. Structural determinants of G protein subtype selectivity at the serotonin receptor 5-HT1A. Sci Adv. 2025;11(31).

2. Mount Sinai Health System. New insights about brain receptor may pave way for next-gen mental health drugs. Newswise. August 4, 2025. Accessed August 5, 2025. https://www.newswise.com/articles/new-insights-about-brain-receptor-may-pave-way-for-next-gen-mental-health-drugs