Visualizing Preference of G Protein-Coupled Receptor Kinase 3 for the Process of κ-Opioid Receptor Sequestration

Schulz, Rüdiger; Wehmeyer, Andrea; Schulz, Karin

doi:10.1124/mol.61.6.1444

Cited by 28 publications

(26 citation statements)

References 33 publications

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“…Similar findings have been reported by other groups using CHO cells, HEK293 cells, or NG108-15 cells expressing the rat or human receptor and U50,488H (Blake et al, 1997b;Jordan et al, 2000;Schulz et al, 2002;McLaughlin et al, 2003). Because pretreatment of the rat and human opioid receptors with U50,488H led to similar levels of AC superactivation, there is no relationship between the degrees of AC superactivation and agonist-induced receptor phosphorylation, desensitization, internalization, and down-regulation.…”

Section: Discussionsupporting

confidence: 71%

“…35 S]GTP␥S binding or inhibition of forskolin-stimulated adenylyl cyclase as the functional endpoint (Blake et al, 1997b;Li et al, 1999Li et al, , 2000Li et al, , 2002Jordan et al, 2000;Schulz et al, 2002;Zhang et al, 2002). In AtT-20 cells or HEK293 cells transfected with the rat receptor-green fluorescence protein, McLaughlin et al (2003) found that the rat receptor was desensitized by 0.1 M U50,488H with agonist-enhanced K ϩ current as the functional endpoint, phosphorylated by 1 M U50,488H, and internalized by 10 M U50,488H.…”

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confidence: 99%

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Differential Effects of Agonists on Adenylyl Cyclase Superactivation Mediated by the κ Opioid Receptors: Adenylyl Cyclase Superactivation Is Independent of Agonist-Induced Phosphorylation, Desensitization, Internalization, and Down-Regulation

Wang

Li²,

Huang³

et al. 2003

J Pharmacol Exp Ther

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Prolonged activation of opioid receptors followed by agonist removal leads to adenylyl cyclase (AC) superactivation. In this study, we examined in CHO cells stably expressing the human or rat opioid receptor (hkor or rkor) whether agonists had differential abilities to induce AC superactivation and whether the hkor and rkor exhibited differential AC superactivation. Pretreatment of the hkor with (trans)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]benzeneacetamide methanesulfonate (U50,488H) induced AC superactivation in a time-and dose-dependent manner, reaching a plateau at 4 h and 0.1 M. The extents of AC superactivation after a 4-h pretreatment of the hkor with saturating concentrations of agonists were in the order of the full agonists U50,488H, dynorphin A(1-17), (Ϯ)-ethylketocyclazocine, etorphine, and U69,593 Ͼ the high-efficacy partial agonist nalorphine Ͼ the low-efficacy partial agonists nalbuphine, morphine, and pentazocine. Interestingly, the full agonist levorphanol caused much lower AC superactivation than other full agonists and reduced the AC superactivation induced by U50,488H and dynorphin A(1-17) in a dose-dependent manner. The order of relative efficacies of agonists in causing AC superactivation mediated by the rkor was similar to that mediated by the hkor and the extents of AC superactivation were slightly lower. Because the rkor does not undergo U50,488H (1 M)-induced phosphorylation, desensitization, internalization, and down-regulation in these cells, the degree of AC superactivation is independent of these processes. This is among the first reports to demonstrate that relative efficacies of agonists in causing AC superactivation generally correlated with those in activating G proteins and a full agonist reduced AC superactivation induced by another full agonist.

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Section: Discussionsupporting

confidence: 71%

mentioning

confidence: 99%

Differential Effects of Agonists on Adenylyl Cyclase Superactivation Mediated by the κ Opioid Receptors: Adenylyl Cyclase Superactivation Is Independent of Agonist-Induced Phosphorylation, Desensitization, Internalization, and Down-Regulation

Wang

Li²,

Huang³

et al. 2003

J Pharmacol Exp Ther

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“…GRK2 primarily targets several GPCRs including ␤-ARs and angiotensin II type 1 receptors, and it is expressed in most tissues. GRK3 targets olfactory receptors, thrombin receptors, kappa-opioid CRF1 (57,219), and ␣1-and ␣2-ARs (12,246). It is found in most tissues, but most prominently in the olfactory epithelium.…”

Section: B Grk Tissue Localizationmentioning

confidence: 99%

The Evolving Impact of G Protein-Coupled Receptor Kinases in Cardiac Health and Disease

Sato

Chuprun

Schwartz

et al. 2015

Physiological Reviews

127

154

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G protein-coupled receptors (GPCRs) are important regulators of various cellular functions via activation of intracellular signaling events. Active GPCR signaling is shut down by GPCR kinases (GRKs) and subsequent β-arrestin-mediated mechanisms including phosphorylation, internalization, and either receptor degradation or resensitization. The seven-member GRK family varies in their structural composition, cellular localization, function, and mechanism of action (see sect. II). Here, we focus our attention on GRKs in particular canonical and novel roles of the GRKs found in the cardiovascular system (see sects. III and IV). Paramount to overall cardiac function is GPCR-mediated signaling provided by the adrenergic system. Overstimulation of the adrenergic system has been highly implicated in various etiologies of cardiovascular disease including hypertension and heart failure. GRKs acting downstream of heightened adrenergic signaling appear to be key players in cardiac homeostasis and disease progression, and herein we review the current data on GRKs related to cardiac disease and discuss their potential in the development of novel therapeutic strategies in cardiac diseases including heart failure.

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“…Using a receptor binding technique, we found that the hkor underwent U50,488H-induced internalization via a GRK-, ␤-arrestin-, and dynamin-dependent process that likely involved clathrincoated vesicles (Li et al, 1999;Zhang et al, 2002). In addition, GRK2 or GRK3 that was co-internalized with the hkor and G protein ␤␥ subunits played a critical role for internalization of the hkor (Schulz et al, 2002). However, unlike U50,488H, etorphine did not promote internalization of the hkor (Li et al, 1999).…”

mentioning

confidence: 99%

Differential Regulation of the Human κ Opioid Receptor by Agonists: Etorphine and Levorphanol Reduced Dynorphin A- and U50,488H-Induced Internalization and Phosphorylation

Zhang²,

Jin³

et al. 2003

J Pharmacol Exp Ther

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We previously observed that (trans)-3,4-dichloro-N-methyl-N- [2-(1-pyrrolidinyl)-cyclohexyl]benzeneacetamide (U50,488H) promoted internalization and phosphorylation of the FLAG-tagged human opioid receptor (FLAG-hkor) stably expressed in Chinese hamster ovary (CHO) cells. In this study, we compared regulation of the FLAG-hkor expressed in CHO cells by U50,488H, dynorphin A, etorphine, and levorphanol, which were potent full agonists as determined by stimulation of guanosine 5Ј-O-(3-[ 35 S]thio)triphosphate binding. Using fluorescence flow cytometry, we found that dynorphin A(1-17), like U50,488H, promoted internalization of the FLAG-hkor in a time-and dose-dependent manner. The antagonists naloxone and norbinaltorphimine, having no effect on FLAG-hkor internalization, effectively blocked dynorphin A(1-17)-and U50,488H-induced internalization. Interestingly, the full agonists etorphine and levorphanol did not cause internalization of the FLAG-hkor but significantly reduced dynorphin A(1-17)-and U50,488H-induced internalization in a dose-dependent manner. Immunofluorescence staining of FLAG-hkor yielded similar results. Dynorphin A(1-17) and U50,488H enhanced phosphorylation of FLAG-hkor to a greater extent than etorphine, but levorphanol did not increase FLAG-hkor phosphorylation. Etorphine or levorphanol decreased dynorphin-or U50,488H-induced phosphorylation. It is likely that conformations of the hkor required for phosphorylation and initiation of internalization are different from those for activation of G proteins. We also examined whether the four agonists had differential effects on superactivation of adenylate cyclase. Pretreatment with U50,488H, dynorphin A(1-17), or etorphine enhanced forskolin-stimulated adenylate cyclase activity to ϳ200 to 250% of the control, whereas levorphanol pretreatment did not result in significant adenylate cyclase superactivation. Thus, the degree of superactivation caused by an agonist is unrelated to its ability to promote internalization of the hkor.

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Visualizing Preference of G Protein-Coupled Receptor Kinase 3 for the Process of κ-Opioid Receptor Sequestration

Cited by 28 publications

References 33 publications

Differential Effects of Agonists on Adenylyl Cyclase Superactivation Mediated by the κ Opioid Receptors: Adenylyl Cyclase Superactivation Is Independent of Agonist-Induced Phosphorylation, Desensitization, Internalization, and Down-Regulation

Differential Effects of Agonists on Adenylyl Cyclase Superactivation Mediated by the κ Opioid Receptors: Adenylyl Cyclase Superactivation Is Independent of Agonist-Induced Phosphorylation, Desensitization, Internalization, and Down-Regulation

The Evolving Impact of G Protein-Coupled Receptor Kinases in Cardiac Health and Disease

Differential Regulation of the Human κ Opioid Receptor by Agonists: Etorphine and Levorphanol Reduced Dynorphin A- and U50,488H-Induced Internalization and Phosphorylation

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