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  Residency time of agonists does not affect the stability of GPCR–arrestin complexes

Mösslein, N., Pohle, L.-M., Fuss, A., Bünemann, M., & Krasel, C. (2022). Residency time of agonists does not affect the stability of GPCR–arrestin complexes. British Journal of Pharmacology. doi:10.1111/bph.15846.

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 Creators:
Mösslein, Nadja1, Author
Pohle, Lisa-Marie2, Author              
Fuss, Anneke1, Author
Bünemann, Moritz1, Author
Krasel, Cornelius1, Author
Affiliations:
1Institute of Pharmacology and Clinical Pharmacy, Philipps University Marburg, Germany, ou_persistent22              
2Max Planck Research Group Pain Perception, MPI for Human Cognitive and Brain Sciences, Max Planck Society, ou_2497695              

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Free keywords: FRAP; FRET; Arrestin trafficking
 Abstract: Background and purpose: The interaction of arrestins with G-protein coupled receptors (GPCRs) desensitizes agonist-dependent receptor responses and often leads to receptor internalization. GPCRs that internalize without arrestin have been classified as "class A" GPCRs whereas "class B" GPCRs co-internalize with arrestin into endosomes. The interaction of arrestins with GPCRs requires both agonist activation and receptor phosphorylation. Here, we ask the question whether agonists with very slow off-rates can cause the formation of particularly stable receptor-arrestin complexes. Experimental approach: The stability of GPCR-arrestin-3 complexes at two class A GPCRs, the β2 -adrenoceptor and the μ opioid receptor, was assessed using two different techniques, fluorescence resonance energy transfer (FRET) and fluorescence recovery after photobleaching (FRAP) employing several ligands with very different off-rates. Arrestin trafficking was determined by confocal microscopy. Key results: Upon agonist washout, GPCR-arrestin-3 complexes showed markedly different dissociation rates in single-cell FRET experiments. In FRAP experiments, however, all full agonists led to the formation of receptor-arrestin complexes of identical stability whereas the complex between the μ receptor and arrestin-3 induced by the partial agonist morphine was less stable. Agonists with very slow off-rates could not mediate the co-internalization of arrestin-3 with class A GPCRs into endosomes. Conclusions and implications: Agonist off-rates do not affect the stability of GPCR-arrestin complexes but phosphorylation patterns do. Our results imply that orthosteric agonists are not able to pharmacologically convert class A into class B GPCRs.

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Language(s): eng - English
 Dates: 2022-04-29
 Publication Status: Published online
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 Table of Contents: -
 Rev. Type: -
 Identifiers: DOI: 10.1111/bph.15846
Other: online ahead of print
PMID: 35352338
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Title: British Journal of Pharmacology
Source Genre: Journal
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Publ. Info: Houndmills, Basingstoke, Hampshire, etc. : Scientific & Medical Division, Macmillan Press, etc.
Pages: - Volume / Issue: - Sequence Number: - Start / End Page: - Identifier: ISSN: 0007-1188
CoNE: https://pure.mpg.de/cone/journals/resource/110992357319090