Role of Phosphorylation Sites in Desensitization of<i>µ</i>-Opioid Receptor

Yousuf, Arsalan; Miess, Elke; Sianati, Setareh; Du, Yanping; Schulz, Stefan; Christie, MacDonald J.

doi:10.1124/mol.115.098244

Cited by 41 publications

(86 citation statements)

References 40 publications

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“…STANT phosphorylation decreases the number of surface receptors, whereas the phosphorylation of TSST inactivates receptors. This is consistent with previous studies identifying multiple parallel pathways that can mediate acute desensitization (Dang et al, 2009) as well as with the companion papers in the current issue that characterize the importance of multiple phosphorylation sites in acute desensitization (Canals, 2015;Yousuf et al, 2015).…”

Section: Discussionsupporting

confidence: 79%

“…Thus, TSST phosphorylation may be strongly biased toward full agonists, such as ME, whereas the unknown portion may demonstrate less bias. This would be consistent with the proposal that morphine and DAMGO can induce MOPr desensitization through different pathways in HEK cells (Johnson et al, 2006;Kelly et al, 2008) and AtT-20 cells (Yousuf et al, 2015).…”

Section: Discussionsupporting

confidence: 79%

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Agonist Binding and Desensitization of the μ-Opioid Receptor Is Modulated by Phosphorylation of the C-Terminal Tail Domain

et al. 2015

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Sustained activation of G protein-coupled receptors can lead to a rapid decline in signaling through acute receptor desensitization. In the case of the m-opioid receptor (MOPr), this desensitization may play a role in the development of analgesic tolerance. It is understood that phosphorylation of MOPr promotes association with b-arrestin proteins, which then facilitates desensitization and receptor internalization. Agonists that induce acute desensitization have been shown to induce a noncanonical high-affinity agonist binding state in MOPr, conferring a persistent memory of prior receptor activation. In the current study, live-cell confocal imaging was used to investigate the role of receptor phosphorylation in agonist binding to MOPr. A phosphorylation cluster in the C-terminal tail of MOPr was identified as a mediator of agonist-induced affinity changes in MOPr. This site is unique from the primary phosphorylation cluster responsible for b-arrestin binding and internalization. Electrophysiologic measurements of receptor function suggest that both phosphorylation clusters may play a parallel role during acute receptor desensitization. Desensitization was unaffected by alanine mutation of either phosphorylation cluster, but was largely eliminated when both clusters were mutated. Overall, this work suggests that there are multiple effects of MOPr phosphorylation that appear to regulate MOPr function: one affecting b-arrestin binding and a second affecting agonist binding.

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Section: Discussionsupporting

confidence: 79%

Section: Discussionsupporting

confidence: 79%

Agonist Binding and Desensitization of the μ-Opioid Receptor Is Modulated by Phosphorylation of the C-Terminal Tail Domain

et al. 2015

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“…However, the impact of the different receptor phosphorylation profiles in the regulation of other aspects of MOPr signaling remains uncertain. In this issue, two independent studies from different groups tackle this important question by using "phosphosite" receptor mutants (Birdsong et al, 2015 andYousuf et al, 2015). Together these studies highlight that agonist-dependent phosphorylation of specific C-terminal motifs participates in the regulation of MOPr signaling via multiple mechanisms that extend beyond b-arrestin recruitment.…”

Section: Introductionmentioning

confidence: 99%

“…Importantly, both studies highlight that 1) desensitization occurs even when the residues required for b-arrestin recruitment are mutated, and 2) the multiple mechanisms participating in MOPr desensitization are ligand dependent and, in some cases, can occur independently of Ser/Thr phosphorylation. Although the contribution of the TSST motif was not directly assessed in the study by Yousuf et al (2015), it is likely that, as suggested by Birdsong et al (2015), the motif participates in MOPr desensitization by stabilizing an uncoupled conformation of the receptor.…”

Section: Introductionmentioning

confidence: 99%

“…In the second study, Yousuf et al (2015) directly assess the role of MOPr phosphorylation in receptor desensitization induced by Met-enkephalin (a high efficacy, internalizing MOPr agonist) or morphine using receptor mutagenesis, perforated patch clamp, and phosphosite specific antibodies in an ATt20 cell background. An important observation is that the rates of MOPr desensitization do not correlate with the rates of receptor phosphorylation.…”

Section: Introductionmentioning

confidence: 99%

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The Complex Roles of μ-Opioid Receptor Phosphorylation: A Key Determinant in Receptor Signaling and Regulation

Canals

2015

Mol Pharmacol

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A cellular perspective of bias at G protein‐coupled receptors

2020

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G protein-coupled receptors (GPCRs) modulate cell function over short-and long-term timescales. GPCR signaling depends on biochemical parameters that define the what, when, and where of receptor function: what proteins mediate and regulate receptor signaling, where within the cell these interactions occur,and how long these interactions persist. These parameters can vary significantly depending on the activating ligand. Collectivity, differential agonist activity at a GPCR is called bias or functional selectivity. Here we review agonist bias at GPCRs with a focus on ligands that show dramatically different cellular responses from their unbiased counterparts.

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Role of Phosphorylation Sites in Desensitization ofµ-Opioid Receptor

Cited by 41 publications

References 40 publications

Agonist Binding and Desensitization of the μ-Opioid Receptor Is Modulated by Phosphorylation of the C-Terminal Tail Domain

Agonist Binding and Desensitization of the μ-Opioid Receptor Is Modulated by Phosphorylation of the C-Terminal Tail Domain

The Complex Roles of μ-Opioid Receptor Phosphorylation: A Key Determinant in Receptor Signaling and Regulation

A cellular perspective of bias at G protein‐coupled receptors

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