Determining the Effects of Differential Expression of GRKs and β-arrestins on CLR-RAMP Agonist Bias.
Poyner, David R
Frontiers Media SA
MetadataShow full item record
Pearce, A., Redfern-Nichols, T., Harris, M., Poyner, D. R., Wigglesworth, M., & Ladds, G. (2022). Determining the Effects of Differential Expression of GRKs and β-arrestins on CLR-RAMP Agonist Bias.. Front Physiol, 13 https://doi.org/10.3389/fphys.2022.840763
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.
CLR, GPCRs (G protein-coupled receptors), GRK (G protein receptor kinase), RAMPs, internalisation, signalling bias, β-arrestins
External DOI: https://doi.org/10.3389/fphys.2022.840763
This record's URL: https://www.repository.cam.ac.uk/handle/1810/337218
Attribution 4.0 International
Licence URL: https://creativecommons.org/licenses/by/4.0/
Recommended or similar items
The current recommendation prototype on the Apollo Repository will be turned off on 03 February 2023. Although the pilot has been fruitful for both parties, the service provider IKVA is focusing on horizon scanning products and so the recommender service can no longer be supported. We recognise the importance of recommender services in supporting research discovery and are evaluating offerings from other service providers. If you would like to offer feedback on this decision please contact us on: email@example.com