Pharmacological characterisation of mouse calcitonin and calcitonin receptor-like receptors reveals differences compared with human receptors.
Adrenomedullin
/ metabolism
Animals
Calcitonin
/ metabolism
Calcitonin Gene-Related Peptide
/ metabolism
Calcitonin Receptor-Like Protein
/ chemistry
Humans
Ligands
Mice
Migraine Disorders
Peptide Hormones
Rats
Receptor Activity-Modifying Protein 1
/ metabolism
Receptor Activity-Modifying Proteins
/ metabolism
Receptors, Adrenomedullin
Receptors, Calcitonin
/ chemistry
CGRP
adrenomedullin
amylin
calcitonin
calcitonin receptor
calcitonin receptor-like receptor
receptor activity-modifying protein
Journal
British journal of pharmacology
ISSN: 1476-5381
Titre abrégé: Br J Pharmacol
Pays: England
ID NLM: 7502536
Informations de publication
Date de publication:
Feb 2022
Feb 2022
Historique:
revised:
17
06
2021
received:
19
03
2021
accepted:
12
07
2021
pubmed:
22
7
2021
medline:
14
4
2022
entrez:
21
7
2021
Statut:
ppublish
Résumé
The calcitonin (CT) receptor family is complex, comprising two receptors (the CT receptor [CTR] and the CTR-like receptor [CLR]), three accessory proteins (RAMPs) and multiple endogenous peptides. This family contains several important drug targets, including CGRP, which is targeted by migraine therapeutics. The pharmacology of this receptor family is poorly characterised in species other than rats and humans. To facilitate understanding of translational and preclinical data, we need to know the receptor pharmacology of this family in mice. Plasmids encoding mouse CLR/CTR and RAMPs were transiently transfected into Cos-7 cells. cAMP production was measured in response to agonists in the absence or presence of antagonists. We report the first synthesis and characterisation of mouse adrenomedullin, adrenomedullin 2 and βCGRP and of mouse CTR without or with mouse RAMPs. Receptors containing m-CTR had subtly different pharmacology than human receptors; they were promiscuous in their pharmacology, both with and without RAMPs. Several peptides, including mouse αCGRP and mouse adrenomedullin 2, were potent agonists of the m-CTR:m-RAMP3 complex. Pharmacological profiles of receptors comprising m-CLR:m-RAMPs were generally similar to those of their human counterparts, albeit with reduced specificity. Mouse receptor pharmacology differed from that in humans, with mouse receptors displaying reduced discrimination between ligands. This creates challenges for interpreting which receptor may underlie an effect in preclinical models and thus translation of findings from mice to humans. It also highlights the need for new ligands to differentiate between these complexes. This article is part of a themed issue on Advances in Migraine and Headache Therapy (BJP 75th Anniversary).. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.3/issuetoc.
Sections du résumé
BACKGROUND AND PURPOSE
OBJECTIVE
The calcitonin (CT) receptor family is complex, comprising two receptors (the CT receptor [CTR] and the CTR-like receptor [CLR]), three accessory proteins (RAMPs) and multiple endogenous peptides. This family contains several important drug targets, including CGRP, which is targeted by migraine therapeutics. The pharmacology of this receptor family is poorly characterised in species other than rats and humans. To facilitate understanding of translational and preclinical data, we need to know the receptor pharmacology of this family in mice.
EXPERIMENTAL APPROACH
METHODS
Plasmids encoding mouse CLR/CTR and RAMPs were transiently transfected into Cos-7 cells. cAMP production was measured in response to agonists in the absence or presence of antagonists.
KEY RESULTS
RESULTS
We report the first synthesis and characterisation of mouse adrenomedullin, adrenomedullin 2 and βCGRP and of mouse CTR without or with mouse RAMPs. Receptors containing m-CTR had subtly different pharmacology than human receptors; they were promiscuous in their pharmacology, both with and without RAMPs. Several peptides, including mouse αCGRP and mouse adrenomedullin 2, were potent agonists of the m-CTR:m-RAMP3 complex. Pharmacological profiles of receptors comprising m-CLR:m-RAMPs were generally similar to those of their human counterparts, albeit with reduced specificity.
CONCLUSION AND IMPLICATIONS
CONCLUSIONS
Mouse receptor pharmacology differed from that in humans, with mouse receptors displaying reduced discrimination between ligands. This creates challenges for interpreting which receptor may underlie an effect in preclinical models and thus translation of findings from mice to humans. It also highlights the need for new ligands to differentiate between these complexes.
LINKED ARTICLES
BACKGROUND
This article is part of a themed issue on Advances in Migraine and Headache Therapy (BJP 75th Anniversary).. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.3/issuetoc.
Identifiants
pubmed: 34289083
doi: 10.1111/bph.15628
pmc: PMC8776895
mid: NIHMS1742484
doi:
Substances chimiques
Calcitonin Receptor-Like Protein
0
Ligands
0
Peptide Hormones
0
Receptor Activity-Modifying Protein 1
0
Receptor Activity-Modifying Proteins
0
Receptors, Adrenomedullin
0
Receptors, Calcitonin
0
Adrenomedullin
148498-78-6
Calcitonin
9007-12-9
Calcitonin Gene-Related Peptide
JHB2QIZ69Z
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
416-434Subventions
Organisme : NINDS NIH HHS
ID : RF1 NS113839
Pays : United States
Informations de copyright
© 2021 The British Pharmacological Society.
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