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Functional modulation of PTH1R activation and signaling by RAMP2

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Item Type:Article
Title:Functional modulation of PTH1R activation and signaling by RAMP2
Creators Name:Nemec, K. and Schihada, H. and Kleinau, G. and Zabel, U. and Grushevsky, E.O. and Scheerer, P. and Lohse, M.J. and Maiellaro, I.
Abstract:Receptor-activity-modifying proteins (RAMPs) are ubiquitously expressed membrane proteins that associate with different G protein-coupled receptors (GPCRs), including the parathyroid hormone 1 receptor (PTH1R), a class B GPCR and an important modulator of mineral ion homeostasis and bone metabolism. However, it is unknown whether and how RAMP proteins may affect PTH1R function. Using different optical biosensors to measure the activation of PTH1R and its downstream signaling, we describe here that RAMP2 acts as a specific allosteric modulator of PTH1R, shifting PTH1R to a unique preactivated state that permits faster activation in a ligand-specific manner. Moreover, RAMP2 modulates PTH1R downstream signaling in an agonist-dependent manner, most notably increasing the PTH-mediated Gi3 signaling sensitivity. Additionally, RAMP2 increases both PTH- and PTHrP-triggered β-arrestin2 recruitment to PTH1R. Employing homology modeling, we describe the putative structural molecular basis underlying our functional findings. These data uncover a critical role of RAMPs in the activation and signaling of a GPCR that may provide a new venue for highly specific modulation of GPCR function and advanced drug design.
Keywords:GPCR, RAMP, BRET, FRET
Source:Proceedings of the National Academy of Sciences of the United States of America
ISSN:0027-8424
Publisher:National Academy of Sciences
Volume:119
Number:32
Page Range:e2122037119
Date:9 August 2022
Official Publication:https://doi.org/10.1073/pnas.2122037119
PubMed:View item in PubMed

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