Determining the Effects of Differential Expression of GRKs and β-arrestins on CLR-RAMP Agonist Bias.
cam.issuedOnline | 2022-03-29 | |
dc.contributor.author | Pearce, Abigail | |
dc.contributor.author | Redfern-Nichols, Theo | |
dc.contributor.author | Harris, Matthew | |
dc.contributor.author | Poyner, David R | |
dc.contributor.author | Wigglesworth, Mark | |
dc.contributor.author | Ladds, Graham | |
dc.contributor.orcid | Pearce, Abigail [0000-0001-9845-0541] | |
dc.contributor.orcid | Harris, Matthew [0000-0002-7918-5735] | |
dc.contributor.orcid | Ladds, Graham [0000-0001-7320-9612] | |
dc.date.accessioned | 2022-05-17T09:03:00Z | |
dc.date.available | 2022-05-17T09:03:00Z | |
dc.date.issued | 2022 | |
dc.date.updated | 2022-05-17T09:03:00Z | |
dc.description.abstract | Signalling 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.identifier.doi | 10.17863/CAM.84636 | |
dc.identifier.eissn | 1664-042X | |
dc.identifier.issn | 1664-042X | |
dc.identifier.other | 35422711 | |
dc.identifier.other | PMC9001978 | |
dc.identifier.uri | https://www.repository.cam.ac.uk/handle/1810/337218 | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | Frontiers Media SA | |
dc.publisher.url | http://dx.doi.org/10.3389/fphys.2022.840763 | |
dc.rights | Attribution 4.0 International | |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0/ | |
dc.source | nlmid: 101549006 | |
dc.source | essn: 1664-042X | |
dc.subject | CLR | |
dc.subject | GPCRs (G protein-coupled receptors) | |
dc.subject | GRK (G protein receptor kinase) | |
dc.subject | RAMPs | |
dc.subject | internalisation | |
dc.subject | signalling bias | |
dc.subject | β-arrestins | |
dc.title | Determining the Effects of Differential Expression of GRKs and β-arrestins on CLR-RAMP Agonist Bias. | |
dc.type | Article | |
dcterms.dateAccepted | 2022-03-08 | |
prism.publicationName | Front Physiol | |
prism.volume | 13 | |
pubs.funder-project-id | BBSRC (BB/V509334/1) | |
pubs.funder-project-id | BBSRC (2471656) | |
rioxxterms.licenseref.uri | https://creativecommons.org/licenses/by/4.0/ | |
rioxxterms.version | VoR | |
rioxxterms.versionofrecord | 10.3389/fphys.2022.840763 |
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