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Functional modulation of PTH1R activation and signaling by RAMP2

Nemec, Katarina; Schihada, Hannes; Kleinau, Gunnar; Zabel, Ulrike; Grushevskyi, Eugene O.; Scheerer, Patrick; Lohse, Martin J.; Maiellaro, Isabella

Authors

Katarina Nemec

Hannes Schihada

Gunnar Kleinau

Ulrike Zabel

Eugene O. Grushevskyi

Patrick Scheerer

Martin J. Lohse



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 agonistdependent 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.

Journal Article Type Article
Acceptance Date Mar 28, 2022
Online Publication Date Aug 1, 2022
Publication Date Aug 9, 2022
Deposit Date Sep 21, 2022
Publicly Available Date Sep 21, 2022
Journal Proceedings of the National Academy of Sciences of the United States of America
Print ISSN 0027-8424
Electronic ISSN 1091-6490
Publisher National Academy of Sciences
Peer Reviewed Peer Reviewed
Volume 119
Issue 32
Article Number e2122037119
DOI https://doi.org/10.1073/pnas.2122037119
Public URL https://nottingham-repository.worktribe.com/output/9589005
Publisher URL https://www.pnas.org/doi/full/10.1073/pnas.2122037119

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