Molecular mechanisms regulating G protein signaling bias

dc.contributor.advisorOrlandi, Cesare
dc.contributor.authorAlabdali, Rana
dc.date.accessioned2025-01-27T06:38:53Z
dc.date.issued2024
dc.description.abstractG 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.extent161
dc.identifier.urihttps://hdl.handle.net/20.500.14154/74751
dc.language.isoen_US
dc.publisherUniversity of Rochester
dc.subjectGPCRs
dc.subjectbiased signaling
dc.subject5-HT
dc.subjectMolecular biases
dc.subjectBRET assay
dc.subjectG proteins
dc.titleMolecular mechanisms regulating G protein signaling bias
dc.typeThesis
sdl.degree.departmentPharmacology and physiology
sdl.degree.disciplineGPCRs
sdl.degree.grantorUniversity of Rochester
sdl.degree.namePhD

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