Journal
BRITISH JOURNAL OF PHARMACOLOGY
Volume 179, Issue 3, Pages 416-434Publisher
WILEY
DOI: 10.1111/bph.15628
Keywords
adrenomedullin; amylin; calcitonin; calcitonin receptor; calcitonin receptor-like receptor; CGRP; receptor activity-modifying protein
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Funding
- Health Research Council of New Zealand
- National Institute of Neurological Disorders and Stroke [NS113839]
- Maurice Wilkins Centre
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The pharmacology of the mouse CLR/CTR and RAMPs receptors differs from that of humans, with mouse receptors showing reduced discrimination between ligands, posing challenges for interpreting data in preclinical models and translating findings from mice to humans. New ligands are needed to differentiate between these complexes.
Background and Purpose 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 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 We report the first synthesis and characterisation of mouse adrenomedullin, adrenomedullin 2 and beta CGRP 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 alpha CGRP 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 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.
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