Summary of the probe development efforts to identify agonists of the mouse 5-hydroxytryptamine (serotonin) receptor 2A (HTR2A)
Name: Summary of the probe development efforts to identify agonists of the mouse 5-hydroxytryptamine (serotonin) receptor 2A (HTR2A). ..more
Source (MLPCN Center Name): The Scripps Research Institute Molecular Screening Center (SRIMSC)
Affiliation: The Scripps Research Institute, TSRI
Assay Provider: Laura Bohn
Network: Molecular Library Probe Production Centers Network (MLPCN)
Grant Proposal Number: DA025158-01A1
Grant Proposal PI: Laura Bohn
External Assay ID: HTR2A_ACT_SUMMARY
Name: Summary of the probe development efforts to identify agonists of the mouse 5-hydroxytryptamine (serotonin) receptor 2A (HTR2A).
Serotonin (5-hydroxytryptamine; 5-HT) is an abundant neurotransmitter synthesized from the essential amino acid L-tryptophan and plays a significant role in appetite, platelet aggregation, pain perception, sleep, hormone secretion, sexual behavior, and thermoregulation. Serotonin mediates much of its actions by binding to and activating G protein-coupled receptors (GPCR) on the surface of neurons and other cells. One of these GPCRs, the serotonin 2A receptor (5-HT2AR), is a 7-transmembrane spanning GPCR in the frontal cortex which impacts on development, anxiety, depression, perception, and cognitive function [1, 2]. In neurons, the 5-HT2AR is a constitutively internalizing receptor and this trafficking is dependent upon interactions with the regulatory protein, B-arrestin2 . Studies in cell-based assays reveal that serotonin requires B-arrestin2 to internalize the receptors while other agonists, such as DOI, 5-MeO-DMT, and quipazine, internalize the receptor in the absence of B-arrestins [3, 4]. All 5-HT2AR agonists seem to recruit B-arrestin2 to 5-HT2AR in cultured cells. However, while serotonin requires B-arrestins to traffic receptors, other agonists such as DOI, 5-MeO-DMT, and quipazine can internalize the receptor in the absence of B-arrestins [3, 4]. It remains to be determined if the specific 5-HT2AR-B-arrestin interactions and trafficking events have physiological significance. It is conceivable that the regulation of 5-HT2AR in vivo may impact neurological sensitivity to serotonin and the responsiveness to pharmacological agents and drugs of abuse. We predict that drugs that disrupt the serotonin 2A receptor-B-arrestin interaction might provide a means to alter the sensitivity of the receptor to the levels of serotonin present in the brain. These findings may inspire the development of drugs that could be clinically useful for treating depression, schizophrenia, and drug addiction [5-7].
Summary of Probe Development Effort:
This probe development effort is focused on the identification of agonists of the mouse 5-hydroxytryptamine (serotonin) receptor 2A (HTR2A). All AIDs that contain results associated with this project can be found in the "Related Bioassays" section of this Summary AID.
1. Hsieh, C.L., A.M. Bowcock, L.A. Farrer, J.M. Hebert, K.N. Huang, L.L. Cavalli-Sforza, D. Julius, and U. Francke, The serotonin receptor subtype 2 locus HTR2 is on human chromosome 13 near genes for esterase D and retinoblastoma-1 and on mouse chromosome 14. Somat Cell Mol Genet, 1990. 16(6): p. 567-74.
2. Berger, M., J.A. Gray, and B.L. Roth, The expanded biology of serotonin. Annu Rev Med, 2009. 60: p. 355-66.
3. Schmid, C.L., K.M. Raehal, and L.M. Bohn, Agonist-directed signaling of the serotonin 2A receptor depends on beta-arrestin-2 interactions in vivo. Proc Natl Acad Sci U S A, 2008. 105(3): p. 1079-84.
4. Bohn, L.M. and C.L. Schmid, Serotonin receptor signaling and regulation via beta-arrestins. Crit Rev Biochem Mol Biol, 2010. 45(6): p. 555-66.
5. Allen, J.A., P.N. Yadav, and B.L. Roth, Insights into the regulation of 5-HT2A serotonin receptors by scaffolding proteins and kinases. Neuropharmacology, 2008. 55(6): p. 961-8.
6. Raehal, K.M. and L.M. Bohn, The role of beta-arrestin2 in the severity of antinociceptive tolerance and physical dependence induced by different opioid pain therapeutics. Neuropharmacology, 2011. 60(1): p. 58-65.
7. Bohn, L.M. and P.H. McDonald, Seeking Ligand Bias: Assessing GPCR Coupling to Beta-Arrestins for Drug Discovery. Drug Discov Today Technol, 2010. 7(1): p. e37-e42.
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