Cholesterol level influences opioid signaling in cell models and analgesia in mice and humans

Zheng, Hui; Zou, Haibo; Liu, Xiaopeng; Chu, Ji; Zhou, Yali; Loh, Horace H.; Law, Ping Yee

doi:10.1194/jlr.m024455

Cited by 33 publications

(37 citation statements)

References 33 publications

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“…Several studies hinted to conformational changes in preexisting dimers and oligomers upon cholesterol depletion (Devost and Zingg, 2004; Paila et al, 2011; Pluhackova et al, 2016). In addition, protein-cholesterol interactions have been reported as essential for efficient GPCR signaling (Nguyen and Taub, 2002, 2003; Zheng et al, 2012b; Jafurulla et al, 2014). Likely, the GPCR dimer equilibrium between both, active and inactive dimers is shifted by the addition/depletion of cholesterol to active/inactive dimers.…”

Section: Discussionmentioning

confidence: 99%

“…By comparing the influence of two different membrane nanodomain disrupting agents, namely simvastatin (reductase that blocks cholesterol synthesis) and D- threo -1-phenyl-2-decanoylamino-3-morpholino-1-propanol (DPDMP, inhibitor that blocks glycosphingolipid synthesis), possible regulation mechanisms of cholesterol in receptor function were investigated (Zheng et al, 2012b). DPDMP disrupted membrane nanodomains without reducing the cholesterol content but did not affect G protein coupling to the μ-opioid receptor, whereas treatment with simvastatin impaired receptor signaling.…”

Section: Specific Membrane Components Influence Gpcr Oligomerizatimentioning

confidence: 99%

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Membrane-Mediated Oligomerization of G Protein Coupled Receptors and Its Implications for GPCR Function

2016

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The dimerization or even oligomerization of G protein coupled receptors (GPCRs) causes ongoing, controversial debates about its functional role and the coupled biophysical, biochemical or biomedical implications. A continously growing number of studies hints to a relation between oligomerization and function of GPCRs and strengthens the assumption that receptor assembly plays a key role in the regulation of protein function. Additionally, progress in the structural analysis of GPCR-G protein and GPCR-ligand interactions allows to distinguish between actively functional and non-signaling complexes. Recent findings further suggest that the surrounding membrane, i.e., its lipid composition may modulate the preferred dimerization interface and as a result the abundance of distinct dimeric conformations. In this review, the association of GPCRs and the role of the membrane in oligomerization will be discussed. An overview of the different reported oligomeric interfaces is provided and their capability for signaling discussed. The currently available data is summarized with regard to the formation of GPCR oligomers, their structures and dependency on the membrane microenvironment as well as the coupling of oligomerization to receptor function.

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Section: Discussionmentioning

confidence: 99%

Section: Specific Membrane Components Influence Gpcr Oligomerizatimentioning

confidence: 99%

Membrane-Mediated Oligomerization of G Protein Coupled Receptors and Its Implications for GPCR Function

2016

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“…Interaction of an opioid receptor with cellular proteins such as ß-arrestin, riboporin1 and GRIN1 will determine its cellular location (84). Translocation of the receptor among microdomains can influence the coupling between the receptor and signaling proteins, such as Gα or ß-arrestin (65, 85). The cellular cholesterol level could not only affect the formation of microdomains such as lipid rafts but could also facilitate the formation of the homodimers and thereby affecting the signaling and the in vivo analgesic responses (86-89).…”

Section: Discussionmentioning

confidence: 99%

Opioid receptors: toward separation of analgesic from undesirable effects

Law

Reggio

Loh

2013

Trends in Biochemical Sciences

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The use of opioid analgesics for pain has always been hampered by their many side effects; in particular, the addictive liability associated with chronic use. Recently, attempts to develop analgesic agents with reduced side effects have targeted either the putative opioid receptor splice variants or the receptor heterooligomers. This review discusses the potential for receptor splice variant- and the hetero-oligomer-based discovery of new opioid analgesics. We also examine an alternative approach of using receptor mutants for pain management. Finally, we discuss the role of the biased agonism observed and the recently reported opioid receptor crystal structures in guiding the future development of opioid analgesics

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“…Cholesterol contributes to opioid receptor signaling via two mechanisms: maintaining the entirety of lipid raft microdomains and directly facilitating opioid receptor signaling [21] . On one hand, the activation of central opioid receptors by selective agonists can stimulate appetite [22] .…”

Section: The Regulation Of Lipid Metabolism By Targeting Opioid Recepmentioning

confidence: 99%

The Regulation of Lipid Metabolism by Targeting Opioid Receptors in Nonalcoholic Fatty Liver Disease

Chung

2017

Journal of Gastroenterology and Hepatology Research

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Cholesterol level influences opioid signaling in cell models and analgesia in mice and humans

Cited by 33 publications

References 33 publications

Membrane-Mediated Oligomerization of G Protein Coupled Receptors and Its Implications for GPCR Function

Membrane-Mediated Oligomerization of G Protein Coupled Receptors and Its Implications for GPCR Function

Opioid receptors: toward separation of analgesic from undesirable effects

The Regulation of Lipid Metabolism by Targeting Opioid Receptors in Nonalcoholic Fatty Liver Disease

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