Enhanced agonist residence time, internalization rate and signalling of the GIP receptor variant [E354Q] facilitate receptor desensitization and long-term impairment of the GIP system

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Enhanced agonist residence time, internalization rate and signalling of the GIP receptor variant [E354Q] facilitate receptor desensitization and long-term impairment of the GIP system. / Gabe, Maria Buur Nordskov; van der Velden, Wijnand J. C.; Gadgaard, Sarina; Smit, Florent Xavier; Hartmann, Bolette; Bräuner-Osborne, Hans; Rosenkilde, Mette Marie.

In: Basic & Clinical Pharmacology & Toxicology, Vol. 126, 2020, p. 122-132.

Research output: Contribution to journalJournal articleResearchpeer-review

Harvard

Gabe, MBN, van der Velden, WJC, Gadgaard, S, Smit, FX, Hartmann, B, Bräuner-Osborne, H & Rosenkilde, MM 2020, 'Enhanced agonist residence time, internalization rate and signalling of the GIP receptor variant [E354Q] facilitate receptor desensitization and long-term impairment of the GIP system', Basic & Clinical Pharmacology & Toxicology, vol. 126, pp. 122-132. https://doi.org/10.1111/bcpt.13289

APA

Gabe, M. B. N., van der Velden, W. J. C., Gadgaard, S., Smit, F. X., Hartmann, B., Bräuner-Osborne, H., & Rosenkilde, M. M. (2020). Enhanced agonist residence time, internalization rate and signalling of the GIP receptor variant [E354Q] facilitate receptor desensitization and long-term impairment of the GIP system. Basic & Clinical Pharmacology & Toxicology, 126, 122-132. https://doi.org/10.1111/bcpt.13289

Vancouver

Gabe MBN, van der Velden WJC, Gadgaard S, Smit FX, Hartmann B, Bräuner-Osborne H et al. Enhanced agonist residence time, internalization rate and signalling of the GIP receptor variant [E354Q] facilitate receptor desensitization and long-term impairment of the GIP system. Basic & Clinical Pharmacology & Toxicology. 2020;126:122-132. https://doi.org/10.1111/bcpt.13289

Author

Gabe, Maria Buur Nordskov ; van der Velden, Wijnand J. C. ; Gadgaard, Sarina ; Smit, Florent Xavier ; Hartmann, Bolette ; Bräuner-Osborne, Hans ; Rosenkilde, Mette Marie. / Enhanced agonist residence time, internalization rate and signalling of the GIP receptor variant [E354Q] facilitate receptor desensitization and long-term impairment of the GIP system. In: Basic & Clinical Pharmacology & Toxicology. 2020 ; Vol. 126. pp. 122-132.

Bibtex

@article{a7ef5032c90a4f27842db6ddbc37f20f,
title = "Enhanced agonist residence time, internalization rate and signalling of the GIP receptor variant [E354Q] facilitate receptor desensitization and long-term impairment of the GIP system",
abstract = "In patients with type 2 diabetes mellitus (T2DM), the insulinotropic action of the GIP system is desensitized, whereas this is not the case for the GLP-1 system. This has raised an interesting discussion of whether GIP agonists or antagonists are most suitable for future treatment of T2DM together with GLP-1-based therapies. Homozygous carriers of the GIP receptor (GIPR) variant, [E354Q], display lower bone mineral density, increased bone fracture risk and slightly increased blood glucose. Here, we present an in-depth molecular pharmacological phenotyping of GIPR-[E354Q]. In silico modelling suggested similar interaction of the endogenous agonist GIP(1-42) to [E354Q] as to GIPR wt. This was supported by homologous competition binding in COS-7 cells revealing GIPR wt-like affinities of GIP(1-42) with K-d values of 2 nmol/L and wt-like agonist association rates (K-on). In contrast, the dissociation rates (K-off) were slower, resulting in 25% higher agonist residence time for GIPR-[E354Q]. Moreover, in G(alpha s) signalling (cAMP production) GIP(1-42) was 2-fold more potent and more efficacious on GIPR-[E354Q] compared to wt with 17.5% higher basal activity. No difference from GIPR wt was found in the recruitment of beta-arrestin 2, whereas the agonist-induced internalization rate was 2.1- to 2.3-fold faster for [E354Q]. Together with the previously described impaired recycling of [E354Q], our findings with enhanced signalling and internalization rate possibly explained by an altered ligand-binding kinetics will lead to receptor desensitization and down-regulation. This could explain the long-term functional impairment of the GIP system in bone metabolism and blood sugar maintenance for [E354Q] carriers and may shed light on the desensitization of the insulinotropic action of GIP in patients with T2DM.",
keywords = "GIP receptor, GIPR-[E354Q], internalization, signalling",
author = "Gabe, {Maria Buur Nordskov} and {van der Velden}, {Wijnand J. C.} and Sarina Gadgaard and Smit, {Florent Xavier} and Bolette Hartmann and Hans Br{\"a}uner-Osborne and Rosenkilde, {Mette Marie}",
note = "Special Issue: MiniReviews and Original Articles from the BCPT‐sponsored Focused Nordic Conference “GPCR Pharmacology – The Next Generation”, held in Copenhagen, Denmark, 31 October to 2 November 2018",
year = "2020",
doi = "10.1111/bcpt.13289",
language = "English",
volume = "126",
pages = "122--132",
journal = "Basic & Clinical Pharmacology & Toxicology",
issn = "1742-7835",
publisher = "Wiley-Blackwell",

}

RIS

TY - JOUR

T1 - Enhanced agonist residence time, internalization rate and signalling of the GIP receptor variant [E354Q] facilitate receptor desensitization and long-term impairment of the GIP system

AU - Gabe, Maria Buur Nordskov

AU - van der Velden, Wijnand J. C.

AU - Gadgaard, Sarina

AU - Smit, Florent Xavier

AU - Hartmann, Bolette

AU - Bräuner-Osborne, Hans

AU - Rosenkilde, Mette Marie

N1 - Special Issue: MiniReviews and Original Articles from the BCPT‐sponsored Focused Nordic Conference “GPCR Pharmacology – The Next Generation”, held in Copenhagen, Denmark, 31 October to 2 November 2018

PY - 2020

Y1 - 2020

N2 - In patients with type 2 diabetes mellitus (T2DM), the insulinotropic action of the GIP system is desensitized, whereas this is not the case for the GLP-1 system. This has raised an interesting discussion of whether GIP agonists or antagonists are most suitable for future treatment of T2DM together with GLP-1-based therapies. Homozygous carriers of the GIP receptor (GIPR) variant, [E354Q], display lower bone mineral density, increased bone fracture risk and slightly increased blood glucose. Here, we present an in-depth molecular pharmacological phenotyping of GIPR-[E354Q]. In silico modelling suggested similar interaction of the endogenous agonist GIP(1-42) to [E354Q] as to GIPR wt. This was supported by homologous competition binding in COS-7 cells revealing GIPR wt-like affinities of GIP(1-42) with K-d values of 2 nmol/L and wt-like agonist association rates (K-on). In contrast, the dissociation rates (K-off) were slower, resulting in 25% higher agonist residence time for GIPR-[E354Q]. Moreover, in G(alpha s) signalling (cAMP production) GIP(1-42) was 2-fold more potent and more efficacious on GIPR-[E354Q] compared to wt with 17.5% higher basal activity. No difference from GIPR wt was found in the recruitment of beta-arrestin 2, whereas the agonist-induced internalization rate was 2.1- to 2.3-fold faster for [E354Q]. Together with the previously described impaired recycling of [E354Q], our findings with enhanced signalling and internalization rate possibly explained by an altered ligand-binding kinetics will lead to receptor desensitization and down-regulation. This could explain the long-term functional impairment of the GIP system in bone metabolism and blood sugar maintenance for [E354Q] carriers and may shed light on the desensitization of the insulinotropic action of GIP in patients with T2DM.

AB - In patients with type 2 diabetes mellitus (T2DM), the insulinotropic action of the GIP system is desensitized, whereas this is not the case for the GLP-1 system. This has raised an interesting discussion of whether GIP agonists or antagonists are most suitable for future treatment of T2DM together with GLP-1-based therapies. Homozygous carriers of the GIP receptor (GIPR) variant, [E354Q], display lower bone mineral density, increased bone fracture risk and slightly increased blood glucose. Here, we present an in-depth molecular pharmacological phenotyping of GIPR-[E354Q]. In silico modelling suggested similar interaction of the endogenous agonist GIP(1-42) to [E354Q] as to GIPR wt. This was supported by homologous competition binding in COS-7 cells revealing GIPR wt-like affinities of GIP(1-42) with K-d values of 2 nmol/L and wt-like agonist association rates (K-on). In contrast, the dissociation rates (K-off) were slower, resulting in 25% higher agonist residence time for GIPR-[E354Q]. Moreover, in G(alpha s) signalling (cAMP production) GIP(1-42) was 2-fold more potent and more efficacious on GIPR-[E354Q] compared to wt with 17.5% higher basal activity. No difference from GIPR wt was found in the recruitment of beta-arrestin 2, whereas the agonist-induced internalization rate was 2.1- to 2.3-fold faster for [E354Q]. Together with the previously described impaired recycling of [E354Q], our findings with enhanced signalling and internalization rate possibly explained by an altered ligand-binding kinetics will lead to receptor desensitization and down-regulation. This could explain the long-term functional impairment of the GIP system in bone metabolism and blood sugar maintenance for [E354Q] carriers and may shed light on the desensitization of the insulinotropic action of GIP in patients with T2DM.

KW - GIP receptor

KW - GIPR-[E354Q]

KW - internalization

KW - signalling

U2 - 10.1111/bcpt.13289

DO - 10.1111/bcpt.13289

M3 - Journal article

C2 - 31299132

VL - 126

SP - 122

EP - 132

JO - Basic & Clinical Pharmacology & Toxicology

JF - Basic & Clinical Pharmacology & Toxicology

SN - 1742-7835

ER -

ID: 227569009