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dc.contributor.authorPearce, Abigail
dc.contributor.authorRedfern-Nichols, Theo
dc.contributor.authorHarris, Matthew
dc.contributor.authorPoyner, David R
dc.contributor.authorWigglesworth, Mark
dc.contributor.authorLadds, Graham
dc.date.accessioned2022-05-17T09:03:00Z
dc.date.available2022-05-17T09:03:00Z
dc.date.issued2022
dc.identifier.issn1664-042X
dc.identifier.other35422711
dc.identifier.otherPMC9001978
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/337218
dc.description.abstractSignalling of the calcitonin-like receptor (CLR) is multifaceted, due to its interaction with receptor activity modifying proteins (RAMPs), and three endogenous peptide agonists. Previous studies have focused on the bias of G protein signalling mediated by the receptor and receptor internalisation of the CLR-RAMP complex has been assumed to follow the same pattern as other Class B1 G Protein-Coupled Receptors (GPCRs). Here we sought to measure desensitisation of the three CLR-RAMP complexes in response to the three peptide agonists, through the measurement of β-arrestin recruitment and internalisation. We then delved further into the mechanism of desensitisation through modulation of β-arrestin activity and the expression of GPCR kinases (GRKs), a key component of homologous GPCR desensitisation. First, we have shown that CLR-RAMP1 is capable of potently recruiting β-arrestin1 and 2, subsequently undergoing rapid endocytosis, and that CLR-RAMP2 and -RAMP3 also utilise these pathways, although to a lesser extent. Following this we have shown that agonist-dependent internalisation of CLR is β-arrestin dependent, but not required for full agonism. Overexpression of GRK2-6 was then found to decrease receptor signalling, due to an agonist-independent reduction in surface expression of the CLR-RAMP complex. These results represent the first systematic analysis of the importance of β-arrestins and GRKs in CLR-RAMP signal transduction and pave the way for further investigation regarding other Class B1 GPCRs.
dc.languageeng
dc.publisherFrontiers Media SA
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.sourcenlmid: 101549006
dc.sourceessn: 1664-042X
dc.subjectInternalisation
dc.subjectClr
dc.subjectΒ-arrestins
dc.subjectRamps
dc.subjectSignalling Bias
dc.subjectGpcrs (G Protein-coupled Receptors)
dc.subjectGrk (G Protein Receptor Kinase)
dc.titleDetermining the Effects of Differential Expression of GRKs and β-arrestins on CLR-RAMP Agonist Bias.
dc.typeArticle
dc.date.updated2022-05-17T09:03:00Z
prism.publicationNameFront Physiol
prism.volume13
dc.identifier.doi10.17863/CAM.84636
dcterms.dateAccepted2022-03-08
rioxxterms.versionofrecord10.3389/fphys.2022.840763
rioxxterms.versionVoR
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0/
dc.contributor.orcidPearce, Abigail [0000-0001-9845-0541]
dc.contributor.orcidHarris, Matthew [0000-0002-7918-5735]
dc.contributor.orcidLadds, Graham [0000-0001-7320-9612]
dc.identifier.eissn1664-042X
pubs.funder-project-idBBSRC (BB/V509334/1)
cam.issuedOnline2022-03-29


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Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International