Mu Opioids Induce Biased Signaling at the Full-Length Seven Transmembrane C-Terminal Splice Variants of the mu Opioid Receptor Gene, Oprm1

Narayan, Ankita; Hunkele, Amanda; Xu, Jin; Bassoni, Daniel L.; Pasternak, Gavril W.; Pan, Ying‐Xian

doi:10.1007/s10571-020-00973-5

Cited by 19 publications

(36 citation statements)

References 55 publications

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“…Together, these results suggest that different intracellular C -terminal tails greatly impact Receptor-G protein coupling induced by the endogenous opioid peptides. It should be pointed out that the influence of the C -terminal tails on G protein coupling was also observed by most mu agonists such as DAMGO, morphine, fentanyl, and methadone [ 73 , 74 , 75 , 76 , 77 , 78 , 79 , 81 ], in contract to their unchanged binding affinity ( Table 2 ). These results suggest the differential effects of the C -terminal tails on ligand binding and G protein activation between endogenous opioid peptides and other mu agonists.…”

Section: G Protein Coupling Induced By Endogenous Opioid Peptides mentioning

confidence: 95%

“…The functional relevance of the full-length 7TM C -terminal variants has been indicated by their differences in mu agonist-induced G protein coupling [ 73 , 74 , 75 , 76 , 77 , 78 , 79 ], β-arrestin2 recruitment [ 80 , 81 ], internalization [ 82 , 83 ], phosphorylation [ 82 ] and post-endocytic sorting [ 84 ] when expressed in cell lines. The 7TM C -terminal variants were differentially expressed in various brain regions or different inbred mouse strains at the mRNA level [ 85 , 86 ], and at the protein level [ 87 , 88 ].…”

Section: Alternative Splicing Of Mu-opioid Receptor Gene Oprm1mentioning

confidence: 99%

“…Several endogenous opioid peptides, including β-endorphin, dynorphin, dynorphin A, [Met] 5 Enkephalin-Arg 6 -Phe 7 , and endomorphins 1/2, as well as several mu opioids such as DAMGO, morphine, fentanyl, buprenorphine and methadone, were used to investigate their abilities to induce β-arrestin2 recruitment on the mouse 7TM C -terminal variants. The results from concentration-response curves unveiled obvious differences in both potency (EC 50 values) and efficacy (% Maximum effect, % E max ) of the endogenous opioid peptides and mu opioids among the 7TM C -terminal variants ( Table 4 ) [ 81 ]. For example, the EC 50 values of [Met] 5 Enkephalin-Arg 6 -Phe 7 and endomorphin-1 had over a 5-fold difference between mMOR-1O and mMOR-1E.…”

Section: Biased Signaling Of Endogenous Opioid Peptides In the Fulmentioning

confidence: 99%

Section: Biased Signaling Of Endogenous Opioid Peptides In the Fulmentioning

confidence: 99%

“…To compare β-arrestin2 recruitment with G protein coupling, [ 35 S]GTPγS binding was performed in the same CHO cells used in the β-arrestin2 recruitment assay [ 81 ]. Again, the endogenous opioid peptides and mu opioids displayed differential profiles of [ 35 S]GTPγS binding among the mouse 7TM variants [ 81 ]. Consequently, the bias factor can be mathematically determined by using the parameters from β-arrestin2 recruitment and [ 35 S]GTPγS binding assays with the operational model of Black and Leff [ 117 , 118 ], a model commonly used in GPCR field, to see if an agonist is β-arrestin2-biased or G protein-biased.…”

Section: Biased Signaling Of Endogenous Opioid Peptides In the Fulmentioning

confidence: 99%

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Endogenous Opioid Peptides and Alternatively Spliced Mu Opioid Receptor Seven Transmembrane Carboxyl-Terminal Variants

Abrimian

Kraft

Pan

2021

IJMS

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There exist three main types of endogenous opioid peptides, enkephalins, dynorphins and β-endorphin, all of which are derived from their precursors. These endogenous opioid peptides act through opioid receptors, including mu opioid receptor (MOR), delta opioid receptor (DOR) and kappa opioid receptor (KOR), and play important roles not only in analgesia, but also many other biological processes such as reward, stress response, feeding and emotion. The MOR gene, OPRM1, undergoes extensive alternative pre-mRNA splicing, generating multiple splice variants or isoforms. One type of these splice variants, the full-length 7 transmembrane (TM) Carboxyl (C)-terminal variants, has the same receptor structures but contains different intracellular C-terminal tails. The pharmacological functions of several endogenous opioid peptides through the mouse, rat and human OPRM1 7TM C-terminal variants have been considerably investigated together with various mu opioid ligands. The current review focuses on the studies of these endogenous opioid peptides and summarizes the results from early pharmacological studies, including receptor binding affinity and G protein activation, and recent studies of β-arrestin2 recruitment and biased signaling, aiming to provide new insights into the mechanisms and functions of endogenous opioid peptides, which are mediated through the OPRM1 7TM C-terminal splice variants.

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Section: G Protein Coupling Induced By Endogenous Opioid Peptides mentioning

confidence: 95%

Section: Alternative Splicing Of Mu-opioid Receptor Gene Oprm1mentioning

confidence: 99%

Section: Biased Signaling Of Endogenous Opioid Peptides In the Fulmentioning

confidence: 99%

Section: Biased Signaling Of Endogenous Opioid Peptides In the Fulmentioning

confidence: 99%

Section: Biased Signaling Of Endogenous Opioid Peptides In the Fulmentioning

confidence: 99%

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Endogenous Opioid Peptides and Alternatively Spliced Mu Opioid Receptor Seven Transmembrane Carboxyl-Terminal Variants

Abrimian

Kraft

Pan

2021

IJMS

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Herkinorin negatively regulates NLRP3 inflammasome to alleviate neuronal ischemic injury through activating Mu opioid receptor and inhibiting the NF‐κB pathway

Cui

et al. 2021

J of Cellular Biochemistry

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Herkinorin is a novel opioid receptor agonist. Activation of opioid receptors, a member of G protein coupled receptors (GPCRs), may play an important role in Herkinorin neuroprotection. GPCRs may modulate NOD‐like receptor protein 3 (NLRP3)‐mediated inflammatory responses in the mechanisms of inflammation‐associated disease and pathological processes. In this study, we investigated the effects of Herkinorin on NLRP3 and the underlying receptor and molecular mechanisms in oxygen‐glucose deprivation/reperfusion (OGD/R)‐treated rat cortex neurons. First, Western blot analysis showed that Herkinorin can inhibit the activation of NLRP3 and Caspase‐1, decrease the expression of interleukin (IL)‐1β, and decrease the secretion of IL‐6 and tumour necrosis factor α detected by enzyme‐linked immunosorbent assay in OGD/R‐treated neurons. Then we found that Herkinorin downregulated NLRP3 levels by inhibiting the activation of nuclear factor kappa B (NF‐κB) pathway, reducing the phosphorylation level of p65 and IκBα in OGD/R‐treated neurons (p < .05 or .01, n = 3 per group). Instead, both the mu opioid receptor (MOR) inhibitor, β‐funaltrexamine, and MOR knockdown reversed the effects of Herkinorin on NLRP3 (p < .05 or .01, n = 3 per group). Further, we found that the level of β‐arrestin2 decreased in the cell membrane and increased in the cytoplasm after Herkinorin pretreatment in OGD/R‐treated neurons. In co‐immunoprecipitation experiments, Herkinorin increased the binding of IκBα with β‐arrestin2, decreased the ubiquitination level of IκBα, and β‐arrestin2 knockdown reversed the effects of Herkinorin on IκBα in OGD/R‐treated neurons (p < .05 or .01, n = 3 per group). Our data demonstrated that Herkinorin negatively regulated NLRP3 inflammasome to alleviate neuronal ischemic injury through inhibiting NF‐κB pathway mediated primarily by MOR activation. Inhibition of the NF‐κB pathway by Herkinorin may be achieved by decreasing the ubiquitination level of IκBα, in which β‐arrestin2 may play an important role.

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Opioid Receptors and Neuronal Signal Transduction

Carranza‐Aguilar

Espinosa-Riquer

Martínez-Cuevas

et al. 2022

Opioids

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Mu Opioids Induce Biased Signaling at the Full-Length Seven Transmembrane C-Terminal Splice Variants of the mu Opioid Receptor Gene, Oprm1

Cited by 19 publications

References 55 publications

Endogenous Opioid Peptides and Alternatively Spliced Mu Opioid Receptor Seven Transmembrane Carboxyl-Terminal Variants

Endogenous Opioid Peptides and Alternatively Spliced Mu Opioid Receptor Seven Transmembrane Carboxyl-Terminal Variants

Herkinorin negatively regulates NLRP3 inflammasome to alleviate neuronal ischemic injury through activating Mu opioid receptor and inhibiting the NF‐κB pathway

Opioid Receptors and Neuronal Signal Transduction

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