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Molecular Mechanisms of PTH/PTHrP Class B GPCR Signaling and Pharmacological Implications.

Vilardaga, Jean-Pierre and Clark, Lisa J and White, Alex D and Sutkeviciute, Ieva and Lee, Ji Young and Bahar, Ivet (2023) Molecular Mechanisms of PTH/PTHrP Class B GPCR Signaling and Pharmacological Implications. Endocr Rev, 44 (3). 474 - 491.

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Abstract

The classical paradigm of G protein-coupled receptor (GPCR) signaling via G proteins is grounded in a view that downstream responses are relatively transient and confined to the cell surface, but this notion has been revised in recent years following the identification of several receptors that engage in sustained signaling responses from subcellular compartments following internalization of the ligand-receptor complex. This phenomenon was initially discovered for the parathyroid hormone (PTH) type 1 receptor (PTH1R), a vital GPCR for maintaining normal calcium and phosphate levels in the body with the paradoxical ability to build or break down bone in response to PTH binding. The diverse biological processes regulated by this receptor are thought to depend on its capacity to mediate diverse modes of cyclic adenosine monophosphate (cAMP) signaling. These include transient signaling at the plasma membrane and sustained signaling from internalized PTH1R within early endosomes mediated by PTH. Here we discuss recent structural, cell signaling, and in vivo studies that unveil potential pharmacological outputs of the spatial versus temporal dimension of PTH1R signaling via cAMP. Notably, the combination of molecular dynamics simulations and elastic network model-based methods revealed how precise modulation of PTH signaling responses is achieved through structure-encoded allosteric coupling within the receptor and between the peptide hormone binding site and the G protein coupling interface. The implications of recent findings are now being explored for addressing key questions on how location bias in receptor signaling contributes to pharmacological functions, and how to drug a difficult target such as the PTH1R toward discovering nonpeptidic small molecule candidates for the treatment of metabolic bone and mineral diseases.


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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Vilardaga, Jean-Pierrejpv@pitt.eduJPV0000-0002-1217-1435
Clark, Lisa J
White, Alex D
Sutkeviciute, Ieva
Lee, Ji Young
Bahar, Ivet
Date: 8 May 2023
Date Type: Publication
Journal or Publication Title: Endocr Rev
Volume: 44
Number: 3
Page Range: 474 - 491
DOI or Unique Handle: 10.1210/endrev/bnac032
Schools and Programs: School of Medicine > Pharmacology and Chemical Biology
Refereed: Yes
Uncontrolled Keywords: G protein–coupled receptor (GPCR), PTH receptor, arrestins, endosomal signaling, location bias, parathyroid hormone, receptor signaling, Humans, Parathyroid Hormone-Related Protein, Parathyroid Hormone, Receptor, Parathyroid Hormone, Type 1, Signal Transduction, Receptors, G-Protein-Coupled, Cyclic AMP
Funders: NIGMS NIH HHS (R01 GM139297), NIDCR NIH HHS (R21 DE032478), NIDDK NIH HHS (R01 DK116780), NIDDK NIH HHS (R01 DK122259)
Date Deposited: 03 Jan 2023 21:03
Last Modified: 12 Dec 2023 06:15
URI: http://d-scholarship.pitt.edu/id/eprint/44071

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