Molecular mechanisms regulating G protein signaling bias
dc.contributor.advisor | Orlandi, Cesare | |
dc.contributor.author | Alabdali, Rana | |
dc.date.accessioned | 2025-01-27T06:38:53Z | |
dc.date.issued | 2024 | |
dc.description.abstract | G Protein Coupled Receptors (GPCRs) are the largest group of membrane receptors in mammals. They are seven transmembrane proteins that couple and transduce signals through heterotrimeric G proteins and β-arrestins which further regulate various downstream signaling pathways. In this context, biased signaling is defined as the ligand-dependent selectivity for certain signal pathways when compared to a reference ligand acting on the same receptor. The most classical example of biased signaling is the functional selectivity between G proteins and β- arrestin. However, signaling bias can also be generated in response to distinct activation of individual Gα proteins leading to different downstream effectors. Therefore, we hypothesize that agonist structure, accessory molecules, and post- transcriptional modifications are three major contributors of G protein signaling bias that in turn regulates unique intracellular effectors and responses. Using cell- based assays, I investigated the effect of agonist structure on serotonin 1A receptor (5-HT1AR) coupling profile using our optimized G protein nanoBRET assay. Also, I examined the effect of accessory lipid such as cholesterol on G protein coupling using 5-HT1AR as model in transfected HEK293 cells. Additionally, I explored the effect of the interaction with the accessory protein receptor component protein (RCP) on the G protein coupling profile of CGRP receptor. Finally, I studied how RNA edited isoforms of serotonin 2C receptor (5- HT2CR) could tune its G protein coupling profile. This would help in understanding how Gα protein preferential selection can potentially alter cellular responses. | |
dc.format.extent | 161 | |
dc.identifier.uri | https://hdl.handle.net/20.500.14154/74751 | |
dc.language.iso | en_US | |
dc.publisher | University of Rochester | |
dc.subject | GPCRs | |
dc.subject | biased signaling | |
dc.subject | 5-HT | |
dc.subject | Molecular biases | |
dc.subject | BRET assay | |
dc.subject | G proteins | |
dc.title | Molecular mechanisms regulating G protein signaling bias | |
dc.type | Thesis | |
sdl.degree.department | Pharmacology and physiology | |
sdl.degree.discipline | GPCRs | |
sdl.degree.grantor | University of Rochester | |
sdl.degree.name | PhD |