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• W4377029651 abstract "<b>Abstract ID 56096</b> <b>Poster Board 138</b> Serotonin 5-HT_2A receptors (5-HT_2ARs) regulate mood and perception in the central nervous system, and are a molecular target for psychedelic hallucinogens, atypical antipsychotics, antidepressants, and anxiolytics. The 5-HT_2AR is a seven transmembrane, G protein-coupled receptor (GPCR) that primarily signals via the Ga_qfamily of heterotrimeric G proteins. Activation of the 5-HT_2AR ultimately results in the intracellular release of Ca²⁺ following Ga_q-mediated activation of phospholipase C (PLC) and the formation of inositol phosphates. In addition to G-protein dependent signaling, many GPCRs are now known to signal through G protein independent pathways. β-Arrestins are intracellular effector proteins that may mediate G protein independent signaling and are known to regulate G protein dependent signaling via receptor endocytosis and recycling at the plasma membrane. However, when compared to other GPCRs, the importance of β-arrestins for controlling the efficacy and duration of 5-HT_2AR signaling is less defined. Live cell confocal imaging utilizing a FLAG-5-HT_2AR and β-arrestin2-GFP was utilized to determine if agonist activation of 5-HT_2AR receptors resulted in the recruitment of β-arrestin to the plasma membrane. Treating cells with either 5-HT (10mM) or the selective 5-HT₂R agonist and hallucinogen DOI (10mM) induced a robust and rapid (within 30 secs) translocation of β-arrestin2-GFP from the cytoplasm to the plasma membrane, where it colocalized with FLAG-5-HT_2AR. To determine the contributions of β-arrestin isoforms in 5-HT_2AR signaling and trafficking, we utilized CRISPR/Cas9 genome editing to stably knockout (KO) β-arrestins 1 and 2. Western blots confirmed a complete loss of the β-arrestin 1 and 2 proteins in KO cells versus parent cells (WT). Using a receptor cell surface ELISA assay, we confirmed a DOI treatment (5 min) resulted in a rapid loss (∼35%) of receptors from the plasma membrane in WT cells. By comparison, 5-HT_2AR endocytosis (3 min to 45 min) was significantly reduced in β-arrestin 1/2 KO cells. Kinetic live-cell Ca²⁺ release by the 5-HT_2AR agonists (5-HT and DOI) was measured using a FLIPR assay. β-arrestin 1/2 KO cells exhibited a prolonged duration of Ca²⁺signaling when compared to WT cells. Additionally, the maximal effect (Emax) of 5-HT and DOI was significantly increased (45% and 46%, respectively) in KO cells, although agonist potency was unchanged. Re-expression of β-arrestin 1 and 2 in KO cells reduced elevated agonist-mediated Ca²⁺ responses to that of WT cells. In addition, knockout of β-arrestin1/2 increased and prolonged the duration of 5-HT_2AR agonist-mediated ERK phosphorylation. Taken together, these data indicate rapid 5-HT_2AR endocytosis following activation a serotonin or hallucinogen agonist is dependent on β-arrestins, and that β-arrestins rapidly interact with 5-HT_2AR receptors to limit both the intensity and duration of Ga_q-mediated signal transduction. Taken together, these studies suggest an essential role of β-arrestins in regulating 5-HT_2AR pharmacodynamics and the signaling responses to both serotonin and a psychedelic hallucinogen." @default.
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• W4377029651 date "2023-05-18" @default.
• W4377029651 modified "2023-09-29" @default.
• W4377029651 title "β-Arrestins Mediate Rapid 5-HT2A Receptor Endocytosis to Control the Efficacy and Kinetics of Serotonin and Psychedelic Hallucinogen Signaling" @default.
• W4377029651 doi "https://doi.org/10.1124/jpet.122.560960" @default.
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