Phosducin, β-arrestin and opioid receptor migration

Schulz, Rüdiger; Wehmeyer, Andrea; Murphy, John J.; Schulz, Karin

doi:10.1016/s0014-2999(99)00223-x

Cited by 20 publications

(14 citation statements)

References 27 publications

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“…These findings are consistent with reports that MOR interacts predominantly with ␤arr-2 in heterologous expression systems (Cheng et al, 1998). Weak interactions of MOR with ␤arr-1 have been reported, particularly when ␤arr-2 is deleted (Schulz et al, 1999), so it is possible that the very small residual desensitization remaining after blocking both ERK1/2 and GRK2-␤arr-2 mechanisms is mediated by ␤arr-1.…”

Section: Discussionsupporting

confidence: 92%

Two Distinct Mechanisms Mediate Acute μ-Opioid Receptor Desensitization in Native Neurons

Dang

Napier²,

Christie³

2009

J. Neurosci.

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Sustained stimulation of G-protein coupled receptors (GPCRs) leads to rapid loss of receptor function (acute desensitization). For manyGPCRs including the -opioid receptor (MOR), an accepted mechanism for acute desensitization is through G-protein coupled receptor kinase (GRKs) mediated phosphorylation of the receptor, which facilitates the binding of ␤-arrestins (␤arrs) to the receptor and then promotes endocytosis. However, the mechanism(s) that mediate acute desensitization have not yet been well defined in native neurons. This study used whole-cell patch clamp recording of G-protein coupled inward-rectifying potassium (GIRK) currents to assay MOR function and identify mechanisms of acute MOR desensitization in locus ceruleus (LC) neurons. The rate and extent of MOR desensitization were unaffected by ␤arr-2 knock-out. Disruption of GRK2 function via inhibitory peptide introduced directly into neurons also failed to affect desensitization in wild type or ␤arr-2 knock-outs. Inhibition of ERK1/2 activation alone had little effect on acute desensitization. However, when both GRK2-␤arr-2 and ERK1/2 functions were disrupted simultaneously, desensitization of MOR was nearly abolished. Together, these results suggest that acute desensitization of MOR in native LC neurons is determined by at least two molecular pathways, one involving GRK2 and ␤arr-2, and a parallel pathway mediated by activated ERK1/2.

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Section: Discussionsupporting

confidence: 92%

Two Distinct Mechanisms Mediate Acute μ-Opioid Receptor Desensitization in Native Neurons

Dang

Napier²,

Christie³

2009

J. Neurosci.

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“…In preliminary experiments, we found that a C-terminal DOR-EGFP fusion shows unchanged binding, signaling, internalization, and down-regulation properties when expressed in HEK 293 cells (Table 1 and Movie 1, which are published as supporting information on the PNAS web site), as suggested in another study (18). We then used homologous recombination to introduce the EGFP cDNA into exon 3 of the Oprd1 mouse gene, in frame and 5Ј from the stop codon ( Fig.…”

Section: Resultssupporting

confidence: 66%

Knockin mice expressing fluorescent δ-opioid receptors uncover G protein-coupled receptor dynamics in vivo

Scherrer

Tryoen-Tóth

Filliol

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

223

275

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The combination of fluorescent genetically encoded proteins with mouse engineering provides a fascinating means to study dynamic biological processes in mammals. At present, green fluorescent protein (GFP) mice were mainly developed to study gene expression patterns or cell morphology and migration. Here we used enhanced GFP (EGFP) to achieve functional imaging of a G proteincoupled receptor (GPCR) in vivo. We created mice where the ␦-opioid receptor (DOR) is replaced by an active DOR-EGFP fusion. Confocal imaging revealed detailed receptor neuroanatomy throughout the nervous system of knockin mice. Real-time imaging in primary neurons allowed dynamic visualization of drug-induced receptor trafficking. In DOR-EGFP animals, drug treatment triggered receptor endocytosis that correlated with the behavioral response. Mice with internalized receptors were insensitive to subsequent agonist administration, providing evidence that receptor sequestration limits drug efficacy in vivo. Direct receptor visualization in mice is a unique approach to receptor biology and drug design.behavioral desensitization ͉ green fluorescent protein ͉ neuroanatomy ͉ real-time imaging ͉ receptor internalization

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“…Like in the brain, strong immunoreactivity for βarrestin-1 was mostly found at postsynaptic densities in the spinal cord (Kittel & Komori 1999). In transfected cellular systems, βarrestin-1 appears to regulate desensitization of numerous GPCRs (Oakley et al 2000), including D1 and D2 dopamine receptors (Kim et al 2001, Oakley et al 2000 and µORs (Oakley et al 2000, Schulz et al 1999; but see Cheng et al 1998). It was found that chronic systemic morphine treatment in rats produced an increase in βarrestin immunoreactivity in the locus coeruleus, measured using an antibody that recognizes both βarrestin-1 and βarrestin-2 (Terwilliger et al 1994).…”

Section: β-Arrestinsmentioning

confidence: 99%

Desensitization of G Protein–coupled Receptors and Neuronal Functions

Gainetdinov

Premont

Bohn

et al. 2004

Annu. Rev. Neurosci.

759

692

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I Abstract G protein-coupled receptors (GPCRs) have proven to be the most highly favorable class of drug targets in modern pharmacology. Over 90% of nonsensory GPCRs are expressed in the brain, where they play important roles in numerous neuronal functions. GPCRs can be desensitized following activation by agonists by becoming phosphorylated by members of the family of G protein-coupled receptor kinases (GRKs). Phosphorylated receptors are then bound by arrestins, which prevent further stimulation of G proteins and downstream signaling pathways. Discussed in this review are recent progress in understanding basics of GPCR desensitization, novel functional roles, patterns of brain expression, and receptor specificity of GRKs and βarrestins in major brain functions. In particular, screening of genetically modified mice lacking individual GRKs or βarrestins for alterations in behavioral and biochemical responses to cocaine and morphine has revealed a functional specificity in dopamine and µ-opioid receptor regulation of locomotion and analgesia. An important and specific role of GRKs and βarrestins in regulating physiological responsiveness to psychostimulants and morphine suggests potential involvement of these molecules in certain brain disorders, such as addiction, Parkinson's disease, mood disorders, and schizophrenia. Furthermore, the utility of a pharmacological strategy aimed at targeting this GPCR desensitization machinery to regulate brain functions can be envisaged.

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Phosducin, β-arrestin and opioid receptor migration

Cited by 20 publications

References 27 publications

Two Distinct Mechanisms Mediate Acute μ-Opioid Receptor Desensitization in Native Neurons

Two Distinct Mechanisms Mediate Acute μ-Opioid Receptor Desensitization in Native Neurons

Knockin mice expressing fluorescent δ-opioid receptors uncover G protein-coupled receptor dynamics in vivo

Desensitization of G Protein–coupled Receptors and Neuronal Functions

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