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dc.contributor.authorJang, Wonjo
dc.date.accessioned2022-03-21T22:03:50Z
dc.date.available2022-03-21T22:03:50Z
dc.identifier.urihttp://hdl.handle.net/10675.2/624267
dc.description.abstractG protein-coupled receptors (GPCRs) are 7-transmembrane (TM) proteins that are targets of one-third of approved drugs. In response to agonist binding, GPCRs adopt active-state conformations that promote their association with G protein heterotrimers. The resulting active-state ternary complex (i.e., agonist-GPCR-G protein complex) is the basis for conventional stimulus-response coupling. However multiple studies have also described GPCR-G protein complexes that form prior to agonist binding. While others have previously proposed that this interaction is thought to promote rapid or specific signaling, the role of such “preassociated” complexes is not well understood, and inactive-state receptors are generally considered unable to interact with heterotrimeric G proteins. Here, we show that preassociation of 5-HT7 serotonin receptors with Gs heterotrimers is necessary for agonist-induced signaling. Because inverse agonists and receptor mutations that favor the inactive state of 5-HT7 receptors promote the formation of preassociated complexes, 5-HT7 receptors in their inactive state preassociate with Gs. Upon agonist binding, 5-HT7 receptors adopt conformations that disfavor the formation of inactive-state 5-HT7–Gs complexes, thus permitting the formation of conventional agonist–5-HT7–Gs ternary complexes. Because Gs variants that cannot form inactive-state 5-HT7-Gs complexes are constitutively activated by 5-HT7 receptors, we conclude that this unconventional inactive-state 5-HT7-Gs complex is critical for the dynamic range of agonist-induced signaling. Thus, our findings provide evidence that agonists can initiate signaling via two distinct mechanisms, by promoting the association of conventional ternary complexes and by disrupting inverse-coupled binary complexes.
dc.publisherAugusta University
dc.subjectNeurosciences
dc.subjectPharmacology
dc.subjectG protein, GPCR, precoupling, serotonin, ternary complex
dc.titleAN INACTIVE RECEPTOR-G PROTEIN COMPLEX MAINTAINS THE DYNAMIC RANGE OF AGONIST-INDUCED SIGNALING
dc.typedissertationen_US
dc.contributor.departmentBiomedical Sciences
dc.language.rfc3066en
dc.date.updated2022-03-21T22:03:50Z
dc.description.advisorLambert, Nevin
dc.description.committeeBlake, David
dc.description.committeeCameron, Richard
dc.description.committeeDhandapani, Krishnan
dc.description.committeeWu, Guangyu
dc.description.degreePh.D.
dc.issued2022-05
refterms.dateFOA2022-05-19T13:01:51Z


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