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Molecular and Cellular Mechanisms Regulating PTH Receptor Signaling and Biology

White, Alex (2020) Molecular and Cellular Mechanisms Regulating PTH Receptor Signaling and Biology. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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G protein-coupled receptors (GPCRs) are the largest family of cell surface proteins that initiate intracellular signaling in response to extracellular stimuli. The classical paradigm of GPCR signaling dictates that downstream responses are relatively transient and confined to the cell surface, but this notion has been challenged in recent years following the identification of several receptors that can engage in sustained G protein-dependent signaling responses from early endosomes following internalization of the ligand-receptor complex. This phenomenon was initially discovered for the parathyroid hormone (PTH) type 1 receptor (PTHR), a class B GPCR that mediates the biological effects of endogenous peptide ligands PTH and its related peptide (PTHrP). Despite significant advancements toward understanding the determinants and relevance of PTHR-mediated endosomal cAMP signaling, this aspect of GPCR signaling remains incompletely understood. Here, we utilize a combination of optical, biochemical, cell biological, and physiological approaches to elucidate novel molecular and cellular mechanisms that underlie endosomal cAMP responses by the PTHR, as well as its biological relevance. We demonstrate that extracellular Ca2+ acts as a positive allosteric modulator of the PTHR by prolonging ligand residence time and increasing the propensity of ligand-receptor complexes to engage in endosomal cAMP generation. We subsequently utilize biased agonism to decode the biological information encoded in the spatial versus temporal dimension of cAMP signaling. Finally, we identify Gq coupling as a critical determinant in PTH-mediated endosomal cAMP production. These findings unveil novel insights into mechanisms and biological outcomes of PTHR-mediated signaling that may prove useful in rational drug design.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
White, Alexalw196@pitt.edualw196
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Thesis AdvisorVilardaga, Jean-Pierre
Committee ChairRomero, Guillermo
Committee MemberXiao, Kunhong
Committee MemberSorkin, Alexander
Committee MemberBisello, Alessandro
Date: 21 May 2020
Date Type: Publication
Defense Date: 13 December 2019
Approval Date: 21 May 2020
Submission Date: 15 May 2020
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Number of Pages: 130
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Molecular Pharmacology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: pharmacology
Date Deposited: 22 May 2020 02:46
Last Modified: 22 May 2020 02:46

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