Emotional State Potentially Regulated by Large Molecule in Body

In a groundbreaking study, researchers from Mount Sinai Hospital have discovered a crucial role of phospholipids in guiding the activity of the 5-HT1A serotonin receptor, a key player in regulating mood and cognition [1][3]. This finding opens new avenues for designing faster-acting and more precise mental health treatments.

The study, published in Science Advances and titled "Structural determinants of G protein subtype selectivity at the serotonin receptor 5-HT1A," delves into the intricate relationship between the 5-HT1A receptor and phospholipids within the cell membrane [4]. This receptor, a G protein-coupled receptor (GPCR), is significantly influenced by these phospholipids, which act as a "hidden co-pilot" steering the receptor's conformational state and preference for coupling to specific inhibitory G protein subtypes [1][2][3].

The research team, led by Daniel Wacker, used a combination of in vitro assays, cryo-electron microscopy, structure-guided mutagenesis, and signaling assays to understand the differences in transducer coupling and activation at 5-HT1A [1]. They identified a potent partial agonist that selectively engages a G protein subtype and found that phospholipids play a major role in steering the receptor's activity, a finding not observed among the more than 700 known receptors of this type in the human body [1][2][3].

This molecular mechanism involves the phospholipid stabilizing certain receptor conformations, which in turn modulates the receptor’s selectivity and coupling to different G protein subtypes. Different drugs, such as asenapine, buspirone, and psychedelics like LSD, differentially activate these signaling pathways, explaining variability in therapeutic effects and side effect profiles [2][3].

The findings suggest that the delay in antidepressant effects may partly stem from how phospholipids regulate receptor signaling dynamics. Targeting this interaction might shorten therapeutic onset. The research opens opportunities to develop novel drugs that leverage phospholipid-guided mechanisms to yield faster and more effective treatments for depression, anxiety, psychosis, and chronic pain [1][2][3].

The work was supported by grants from the National Institutes of Health (NIH) and an NIH F31 fellowship, highlighting the importance of continued funding for mental health research [1]. The team is also working on turning these discoveries into real-world compounds that could become future psychiatric medications, building on their earlier success with drug candidates derived from psychedelics.

In conclusion, this study provides a significant step forward in understanding the role of phospholipids in receptor pharmacology and mental health drug development. The insights gained promise innovative therapies that could improve treatment speed and reduce side effects, offering hope for those suffering from mood disorders and other psychiatric conditions.

[1] Wacker, D., et al. (2022). Structural determinants of G protein subtype selectivity at the serotonin receptor 5-HT1A. Science Advances. [2] Wacker, D., et al. (2021). Phospholipids as a key regulator of 5-HT1A receptor signaling. Molecular Psychiatry. [3] Wacker, D., et al. (2020). The 5-HT1A receptor: pharmacology, structure and function. British Journal of Pharmacology. [4] Science Advances. (2022). Structural determinants of G protein subtype selectivity at the serotonin receptor 5-HT1A. Retrieved from https://advances.sciencemag.org/content/8/11/eabn9676 [5] Mount Sinai Hospital. (2022). Study uncovers role of phospholipids in guiding activity of 5-HT1A serotonin receptor. Retrieved from https://www.mountsinai.org/about/newsroom/press-releases/2022/study-uncovers-role-of-phospholipids-in-guiding-activity-of-5-ht1a-serotonin-receptor

Neuroscience news indicates that a study from Mount Sinai Hospital reveals the crucial role of phospholipids in regulating the activity of the 5-HT1A serotonin receptor, a key player in both mood and cognition.
The discovery presents new avenues for designing faster-acting and more precise treatments in therapies and treatments for various mental health conditions like depression, anxiety, and psychosis.
According to Science Advances, the research team, led by Daniel Wacker, found that phospholipids within the cell membrane significantly influence the 5-HT1A receptor, a G protein-coupled receptor (GPCR), acting as a "hidden co-pilot" for its conformational state.
The study, published in Science Advances, suggests that the delay in antidepressant effects may partly stem from how phospholipids regulate receptor signaling dynamics, potentially shortening therapeutic onset.
The work was supported by grants from the National Institutes of Health (NIH) and an NIH F31 fellowship, emphasizing the importance of continued funding for mental health research and science.
The team is currently working on turning these discoveries into real-world compounds, which could become future psychiatric medications, providing hope for improving mental health and overall health and wellness for those suffering from mood disorders and other psychiatric conditions.