Spatiotemporal GLP-1 and GIP receptor signaling and trafficking/recycling dynamics induced by selected receptor mono- and dual-agonists

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Standard

Spatiotemporal GLP-1 and GIP receptor signaling and trafficking/recycling dynamics induced by selected receptor mono- and dual-agonists. / Novikoff, Aaron; O'Brien, Shannon L; Bernecker, Miriam; Grandl, Gerald; Kleinert, Maximilian; Knerr, Patrick J; Stemmer, Kerstin; Klingenspor, Martin; Zeigerer, Anja; DiMarchi, Richard; Tschöp, Matthias H; Finan, Brian; Calebiro, Davide; Müller, Timo D.

I: Molecular Metabolism, Bind 49, 101181, 2021.

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt

Harvard

Novikoff, A, O'Brien, SL, Bernecker, M, Grandl, G, Kleinert, M, Knerr, PJ, Stemmer, K, Klingenspor, M, Zeigerer, A, DiMarchi, R, Tschöp, MH, Finan, B, Calebiro, D & Müller, TD 2021, 'Spatiotemporal GLP-1 and GIP receptor signaling and trafficking/recycling dynamics induced by selected receptor mono- and dual-agonists', Molecular Metabolism, bind 49, 101181. https://doi.org/10.1016/j.molmet.2021.101181

APA

Novikoff, A., O'Brien, S. L., Bernecker, M., Grandl, G., Kleinert, M., Knerr, P. J., Stemmer, K., Klingenspor, M., Zeigerer, A., DiMarchi, R., Tschöp, M. H., Finan, B., Calebiro, D., & Müller, T. D. (2021). Spatiotemporal GLP-1 and GIP receptor signaling and trafficking/recycling dynamics induced by selected receptor mono- and dual-agonists. Molecular Metabolism, 49, [101181]. https://doi.org/10.1016/j.molmet.2021.101181

Vancouver

Novikoff A, O'Brien SL, Bernecker M, Grandl G, Kleinert M, Knerr PJ o.a. Spatiotemporal GLP-1 and GIP receptor signaling and trafficking/recycling dynamics induced by selected receptor mono- and dual-agonists. Molecular Metabolism. 2021;49. 101181. https://doi.org/10.1016/j.molmet.2021.101181

Author

Novikoff, Aaron ; O'Brien, Shannon L ; Bernecker, Miriam ; Grandl, Gerald ; Kleinert, Maximilian ; Knerr, Patrick J ; Stemmer, Kerstin ; Klingenspor, Martin ; Zeigerer, Anja ; DiMarchi, Richard ; Tschöp, Matthias H ; Finan, Brian ; Calebiro, Davide ; Müller, Timo D. / Spatiotemporal GLP-1 and GIP receptor signaling and trafficking/recycling dynamics induced by selected receptor mono- and dual-agonists. I: Molecular Metabolism. 2021 ; Bind 49.

Bibtex

@article{4e54425efd144a21833add6ed421ae62,
title = "Spatiotemporal GLP-1 and GIP receptor signaling and trafficking/recycling dynamics induced by selected receptor mono- and dual-agonists",
abstract = "Objective: We assessed the spatiotemporal GLP-1 and GIP receptor signaling, trafficking, and recycling dynamics of GIPR mono-agonists, GLP-1R mono-agonists including semaglutide, and GLP-1/GIP dual-agonists MAR709 and tirzepatide. Methods: Receptor G protein recruitment and internalization /trafficking dynamics were assessed using bioluminescence resonance energy transfer (BRET)-based technology and live-cell HILO microscopy. Results: Relative to native and acylated GLP-1 agonists, MAR709 and tirzepatide showed preserved maximal cAMP production despite partial Gαs recruitment paralleled by diminished ligand-induced receptor internalization at both target receptors. Despite MAR709's lower internalization rate, GLP-1R co-localization with Rab11-associated recycling endosomes was not different between MAR709 and GLP-1R specific mono-agonists. Conclusions: Our data indicated that MAR709 and tirzepatide induce unique spatiotemporal GLP-1 and GIP receptor signaling, trafficking, and recycling dynamics relative to native peptides, semaglutide, and matched mono-agonist controls. These findings support the hypothesis that the structure of GLP-1/GIP dual-agonists confer a biased agonism that, in addition to its influence on intracellular signaling, uniquely modulates receptor trafficking.",
keywords = "Biased agonism, Dual-agonists, GIPR, GLP-1R, Receptor internalization, Receptor trafficking",
author = "Aaron Novikoff and O'Brien, {Shannon L} and Miriam Bernecker and Gerald Grandl and Maximilian Kleinert and Knerr, {Patrick J} and Kerstin Stemmer and Martin Klingenspor and Anja Zeigerer and Richard DiMarchi and Tsch{\"o}p, {Matthias H} and Brian Finan and Davide Calebiro and M{\"u}ller, {Timo D}",
note = "(Ekstern)",
year = "2021",
doi = "10.1016/j.molmet.2021.101181",
language = "English",
volume = "49",
journal = "Molecular Metabolism",
issn = "2212-8778",
publisher = "Elsevier",

}

RIS

TY - JOUR

T1 - Spatiotemporal GLP-1 and GIP receptor signaling and trafficking/recycling dynamics induced by selected receptor mono- and dual-agonists

AU - Novikoff, Aaron

AU - O'Brien, Shannon L

AU - Bernecker, Miriam

AU - Grandl, Gerald

AU - Kleinert, Maximilian

AU - Knerr, Patrick J

AU - Stemmer, Kerstin

AU - Klingenspor, Martin

AU - Zeigerer, Anja

AU - DiMarchi, Richard

AU - Tschöp, Matthias H

AU - Finan, Brian

AU - Calebiro, Davide

AU - Müller, Timo D

N1 - (Ekstern)

PY - 2021

Y1 - 2021

N2 - Objective: We assessed the spatiotemporal GLP-1 and GIP receptor signaling, trafficking, and recycling dynamics of GIPR mono-agonists, GLP-1R mono-agonists including semaglutide, and GLP-1/GIP dual-agonists MAR709 and tirzepatide. Methods: Receptor G protein recruitment and internalization /trafficking dynamics were assessed using bioluminescence resonance energy transfer (BRET)-based technology and live-cell HILO microscopy. Results: Relative to native and acylated GLP-1 agonists, MAR709 and tirzepatide showed preserved maximal cAMP production despite partial Gαs recruitment paralleled by diminished ligand-induced receptor internalization at both target receptors. Despite MAR709's lower internalization rate, GLP-1R co-localization with Rab11-associated recycling endosomes was not different between MAR709 and GLP-1R specific mono-agonists. Conclusions: Our data indicated that MAR709 and tirzepatide induce unique spatiotemporal GLP-1 and GIP receptor signaling, trafficking, and recycling dynamics relative to native peptides, semaglutide, and matched mono-agonist controls. These findings support the hypothesis that the structure of GLP-1/GIP dual-agonists confer a biased agonism that, in addition to its influence on intracellular signaling, uniquely modulates receptor trafficking.

AB - Objective: We assessed the spatiotemporal GLP-1 and GIP receptor signaling, trafficking, and recycling dynamics of GIPR mono-agonists, GLP-1R mono-agonists including semaglutide, and GLP-1/GIP dual-agonists MAR709 and tirzepatide. Methods: Receptor G protein recruitment and internalization /trafficking dynamics were assessed using bioluminescence resonance energy transfer (BRET)-based technology and live-cell HILO microscopy. Results: Relative to native and acylated GLP-1 agonists, MAR709 and tirzepatide showed preserved maximal cAMP production despite partial Gαs recruitment paralleled by diminished ligand-induced receptor internalization at both target receptors. Despite MAR709's lower internalization rate, GLP-1R co-localization with Rab11-associated recycling endosomes was not different between MAR709 and GLP-1R specific mono-agonists. Conclusions: Our data indicated that MAR709 and tirzepatide induce unique spatiotemporal GLP-1 and GIP receptor signaling, trafficking, and recycling dynamics relative to native peptides, semaglutide, and matched mono-agonist controls. These findings support the hypothesis that the structure of GLP-1/GIP dual-agonists confer a biased agonism that, in addition to its influence on intracellular signaling, uniquely modulates receptor trafficking.

KW - Biased agonism

KW - Dual-agonists

KW - GIPR

KW - GLP-1R

KW - Receptor internalization

KW - Receptor trafficking

UR - http://www.scopus.com/inward/record.url?scp=85101615958&partnerID=8YFLogxK

U2 - 10.1016/j.molmet.2021.101181

DO - 10.1016/j.molmet.2021.101181

M3 - Journal article

C2 - 33556643

AN - SCOPUS:85101615958

VL - 49

JO - Molecular Metabolism

JF - Molecular Metabolism

SN - 2212-8778

M1 - 101181

ER -

ID: 258718052