Drugs which target serotonin receptors are useful for treating virtually every psychiatric disorder and many major medical disorders. The overall goals of this application are to determine how certain serotonin receptors (htr2A and htr2C) are regulated by the processes of neuronal targeting, trafficking and phosophorylation-induced post-translational processing. In the first two specific aims, the relevance of interactions with PDZ-domain proteins for controlling the neuronal targeting, trafficking and signaling of 5-HT2A and 5-HT2C receptors will be elucidated. For these studies we will use murine genetic deletion approaches (constitutive and conditional) and novel protein microarray-based approaches to discover and validate PDZ-domain protein interactions. We will also utilize in utero electroporation approaches and mouse genetic engineering approaches to determine how PDZ-binding motifs modulate 5-HT2A function in situ and in vivo. Similar studies may also be performed with 5-HT2C receptors. In the third specific aim we will determine if RSK2 modulates neuronal 5-HT2A receptor signaling and function in vitro and in vivo. In this specific aim we will utilize a variety of in vitro and in vivo approaches involving wild-type, 5-HT2A KO (constitutive and conditional) and RSK2 KO mice. We will clarify the role RSK2 plays in regulating 5-HT2A receptor signaling in neuronal and non-neuronal tissues in vitro and in vivo. Because these receptors are essential for the actions of many psychiatric and non-psychiatric medications including atypical antipsychotics, certain antidepressants, hallucinogens and some appetite suppressants our studies could lead to novel therapeutic strategies for many therapeutic indications.

Public Health Relevance

Drugs which target serotonin receptors are useful for treating virtually every psychiatric disorder and many major medical disorders. This grant will elucidate the mechanisms by which serotonin receptors are targeted to different neuronal locations. This knowledge will help to clarify the mechanism by which these medications are effective in alleviating human illness.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
Project #
Application #
Study Section
Molecular Neuropharmacology and Signaling Study Section (MNPS)
Program Officer
Nadler, Laurie S
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of North Carolina Chapel Hill
Schools of Medicine
Chapel Hill
United States
Zip Code
Che, Tao; Majumdar, Susruta; Zaidi, Saheem A et al. (2018) Structure of the Nanobody-Stabilized Active State of the Kappa Opioid Receptor. Cell 172:55-67.e15
Wang, Sheng; Che, Tao; Levit, Anat et al. (2018) Structure of the D2 dopamine receptor bound to the atypical antipsychotic drug risperidone. Nature 555:269-273
McCorvy, John D; Wacker, Daniel; Wang, Sheng et al. (2018) Structural determinants of 5-HT2B receptor activation and biased agonism. Nat Struct Mol Biol 25:787-796
Wacker, Daniel; Wang, Sheng; McCorvy, John D et al. (2017) Crystal Structure of an LSD-Bound Human Serotonin Receptor. Cell 168:377-389.e12
Farrell, Martilias S; McCorvy, John D; Huang, Xi-Ping et al. (2016) In Vitro and In Vivo Characterization of the Alkaloid Nuciferine. PLoS One 11:e0150602
Urban, Daniel J; Zhu, Hu; Marcinkiewcz, Catherine A et al. (2016) Elucidation of The Behavioral Program and Neuronal Network Encoded by Dorsal Raphe Serotonergic Neurons. Neuropsychopharmacology 41:1404-15
McCorvy, John D; Roth, Bryan L (2015) Structure and function of serotonin G protein-coupled receptors. Pharmacol Ther 150:129-42
Roth, Bryan L; Kroeze, Wesley K (2015) Integrated Approaches for Genome-wide Interrogation of the Druggable Non-olfactory G Protein-coupled Receptor Superfamily. J Biol Chem 290:19471-7
Nocjar, C; Alex, K D; Sonneborn, A et al. (2015) Serotonin-2C and -2a receptor co-expression on cells in the rat medial prefrontal cortex. Neuroscience 297:22-37
Giguere, Patrick M; Kroeze, Wesley K; Roth, Bryan L (2014) Tuning up the right signal: chemical and genetic approaches to study GPCR functions. Curr Opin Cell Biol 27:51-5

Showing the most recent 10 out of 91 publications