CGRP, adrenomedullin and adrenomedullin 2 display endogenous GPCR agonist bias in primary human cardiovascular cells

Ashley Clark; Niamh Mullooly; Dewi Safitri; Matthew Harris; Tessa de Vries; Antoinette Maassen Van Den Brink; David Poyner; Davide Gianni; Mark Wrigglesworth; Graham Ladds

doi:10.1038/s42003-021-02293-w

CGRP, adrenomedullin and adrenomedullin 2 display endogenous GPCR agonist bias in primary human cardiovascular cells

Ashley Clark, Niamh Mullooly, Dewi Safitri, Matthew Harris, Tessa de Vries, Antoinette Maassen Van Den Brink, David Poyner, Davide Gianni, Mark Wrigglesworth, Graham Ladds^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

Abstract

Agonist bias occurs when different ligands produce distinct signalling outputs when acting at the same receptor. However, its physiological relevance is not always clear. Using primary human cells and gene editing techniques, we demonstrate for the first time, endogenous agonist bias with physiological consequences for the calcitonin receptor-like receptor, CLR. By switching the receptor activity modifying protein (RAMP) associated with CLR we can“re-route” the physiological pathways activated by endogenous agonists calcitonin gene related peptide (CGRP), adrenomedullin (AM) and adrenomedullin 2 (AM2). AM2 promotes calcium-mediated nitric oxide signalling whereas CGRP and AM show pro-proliferative effects in cardiovascular cells, thus providing a rationale for the expression of the three peptides. CLR-based agonist bias occurs naturally in human cells and has a fundamental purpose for its existence. We anticipate this will be a starting point for more studies into RAMP function in native environments and their importance in endogenous GPCR signalling

Original language	English
Article number	776
Journal	Communications Biology
Volume	4
DOIs	https://doi.org/10.1038/s42003-021-02293-w
Publication status	Published - 23 Jun 2021

Bibliographical note

This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

Funding: This work was supported by the Biotechnology and Biological Sciences Research Council [grant number BB/M000176/2] awarded to GL and DRP, a Medical Research Council Confidence in Concept award to GL and MH (MC_PC_17156) and the Endowment Fund for education from Ministry of Finance Republic of Indonesia (DS). AJC is funded through an AstraZeneca Scholarship.

Keywords

Calcitonin
Receptor pharmacology

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10.1038/s42003-021-02293-wLicence: CC BY 3.0

CGRP, adrenomedullin and adrenomedullin 2 display endogenous GPCR
This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Final published version, 3.12 MBLicence: CC BY 3.0

Cite this

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title = "CGRP, adrenomedullin and adrenomedullin 2 display endogenous GPCR agonist bias in primary human cardiovascular cells",

abstract = "Agonist bias occurs when different ligands produce distinct signalling outputs when acting at the same receptor. However, its physiological relevance is not always clear. Using primary human cells and gene editing techniques, we demonstrate for the first time, endogenous agonist bias with physiological consequences for the calcitonin receptor-like receptor, CLR. By switching the receptor activity modifying protein (RAMP) associated with CLR we can“re-route” the physiological pathways activated by endogenous agonists calcitonin gene related peptide (CGRP), adrenomedullin (AM) and adrenomedullin 2 (AM2). AM2 promotes calcium-mediated nitric oxide signalling whereas CGRP and AM show pro-proliferative effects in cardiovascular cells, thus providing a rationale for the expression of the three peptides. CLR-based agonist bias occurs naturally in human cells and has a fundamental purpose for its existence. We anticipate this will be a starting point for more studies into RAMP function in native environments and their importance in endogenous GPCR signalling",

keywords = "Calcitonin, Receptor pharmacology",

author = "Ashley Clark and Niamh Mullooly and Dewi Safitri and Matthew Harris and {de Vries}, Tessa and {Maassen Van Den Brink}, Antoinette and David Poyner and Davide Gianni and Mark Wrigglesworth and Graham Ladds",

note = "This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article{\textquoteright}s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article{\textquoteright}s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Funding: This work was supported by the Biotechnology and Biological Sciences Research Council [grant number BB/M000176/2] awarded to GL and DRP, a Medical Research Council Confidence in Concept award to GL and MH (MC_PC_17156) and the Endowment Fund for education from Ministry of Finance Republic of Indonesia (DS). AJC is funded through an AstraZeneca Scholarship.",

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AU - Clark, Ashley

AU - Mullooly, Niamh

AU - Safitri, Dewi

AU - Harris, Matthew

AU - de Vries, Tessa

AU - Maassen Van Den Brink, Antoinette

AU - Poyner, David

AU - Gianni, Davide

AU - Wrigglesworth, Mark

AU - Ladds, Graham

N1 - This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Funding: This work was supported by the Biotechnology and Biological Sciences Research Council [grant number BB/M000176/2] awarded to GL and DRP, a Medical Research Council Confidence in Concept award to GL and MH (MC_PC_17156) and the Endowment Fund for education from Ministry of Finance Republic of Indonesia (DS). AJC is funded through an AstraZeneca Scholarship.

PY - 2021/6/23

Y1 - 2021/6/23

N2 - Agonist bias occurs when different ligands produce distinct signalling outputs when acting at the same receptor. However, its physiological relevance is not always clear. Using primary human cells and gene editing techniques, we demonstrate for the first time, endogenous agonist bias with physiological consequences for the calcitonin receptor-like receptor, CLR. By switching the receptor activity modifying protein (RAMP) associated with CLR we can“re-route” the physiological pathways activated by endogenous agonists calcitonin gene related peptide (CGRP), adrenomedullin (AM) and adrenomedullin 2 (AM2). AM2 promotes calcium-mediated nitric oxide signalling whereas CGRP and AM show pro-proliferative effects in cardiovascular cells, thus providing a rationale for the expression of the three peptides. CLR-based agonist bias occurs naturally in human cells and has a fundamental purpose for its existence. We anticipate this will be a starting point for more studies into RAMP function in native environments and their importance in endogenous GPCR signalling

AB - Agonist bias occurs when different ligands produce distinct signalling outputs when acting at the same receptor. However, its physiological relevance is not always clear. Using primary human cells and gene editing techniques, we demonstrate for the first time, endogenous agonist bias with physiological consequences for the calcitonin receptor-like receptor, CLR. By switching the receptor activity modifying protein (RAMP) associated with CLR we can“re-route” the physiological pathways activated by endogenous agonists calcitonin gene related peptide (CGRP), adrenomedullin (AM) and adrenomedullin 2 (AM2). AM2 promotes calcium-mediated nitric oxide signalling whereas CGRP and AM show pro-proliferative effects in cardiovascular cells, thus providing a rationale for the expression of the three peptides. CLR-based agonist bias occurs naturally in human cells and has a fundamental purpose for its existence. We anticipate this will be a starting point for more studies into RAMP function in native environments and their importance in endogenous GPCR signalling

KW - Calcitonin

KW - Receptor pharmacology

UR - https://www.nature.com/articles/s42003-021-02293-w

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U2 - 10.1038/s42003-021-02293-w

DO - 10.1038/s42003-021-02293-w

M3 - Article

C2 - 34163006

SN - 2399-3642

VL - 4

JO - Communications Biology

JF - Communications Biology

M1 - 776

ER -

CGRP, adrenomedullin and adrenomedullin 2 display endogenous GPCR agonist bias in primary human cardiovascular cells

Abstract

Bibliographical note

Keywords

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