Dual RXR motifs regulate nerve growth factor–mediated intracellular retention of the delta opioid receptor

The delta opioid receptor (DOR), a physiologically relevant prototype for G protein–coupled receptors, is retained in intracellular compartments in neuronal cells. This retention is mediated by a nerve growth factor (NGF)-regulated checkpoint that delays the export of DOR from the trans-Golgi network. How DOR is selectively retained in the Golgi, in the midst of dynamic membrane transport and cargo export, is a fundamental unanswered question. Here we address this by investigating sequence elements on DOR that regulate DOR surface delivery, focusing on the C-terminal tail of DOR that is sufficient for NGF-mediated regulation. By systematic mutational analysis, we define conserved dual bi-arginine (RXR) motifs that are required for NGF- and phosphoinositide-regulated DOR export from intracellular compartments in neuroendocrine cells. These motifs were required to bind the coatomer protein I (COPI) complex, a vesicle coat complex that mediates primarily retrograde cargo traffic in the Golgi. Our results suggest that interactions of DOR with COPI, via atypical COPI motifs on the C-terminal tail, retain DOR in the Golgi. These interactions could provide a point of regulation of DOR export and delivery by extracellular signaling pathways.

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Crosstalk between Delta Opioid Receptor and Nerve Growth Factor Signaling Modulates Neuroprotection and Differentiation in Rodent Cell Models

International Journal of Molecular Sciences ◽

10.3390/ijms141021114 ◽

2013 ◽

Vol 14 (10) ◽

pp. 21114-21139 ◽

Cited By ~ 16

Author(s):

Dwaipayan Sen ◽

Michael Huchital ◽

Yulong Chen

Keyword(s):

Nerve Growth Factor ◽

Growth Factor ◽

Opioid Receptor ◽

Delta Opioid Receptor ◽

Growth Factor Signaling ◽

Cell Models ◽

Nerve Growth ◽

Rodent Cell

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Impacts of anti-nerve growth factor antibody on pain-related behaviors and expressions of opioid receptor in spinal dorsal horn and dorsal root ganglia of rats with cancer-induced bone pain

Molecular Pain ◽

10.1177/1744806916644928 ◽

2016 ◽

Vol 12 ◽

pp. 174480691664492 ◽

Cited By ~ 9

Author(s):

Peng Yao ◽

Yuanyuan Ding ◽

Zhibin Wang ◽

Jiaming Ma ◽

Tao Hong ◽

...

Keyword(s):

Nerve Growth Factor ◽

Growth Factor ◽

Dorsal Horn ◽

Opioid Receptor ◽

Dorsal Root Ganglia ◽

Dorsal Root ◽

Spinal Dorsal Horn ◽

Bone Pain ◽

Nerve Growth ◽

Spinal Dorsal

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Activation of codependent transcription factors is required for transcriptional induction of the vgf gene by nerve growth factor and Ras.

Molecular and Cellular Biology ◽

10.1128/mcb.16.9.4621 ◽

1996 ◽

Vol 16 (9) ◽

pp. 4621-4631 ◽

Cited By ~ 23

Author(s):

G D'Arcangelo ◽

R Habas ◽

S Wang ◽

S Halegoua ◽

S R Salton

Keyword(s):

Transcription Factor ◽

Transcription Factors ◽

Nerve Growth Factor ◽

Growth Factor ◽

Pc12 Cells ◽

Mutational Analysis ◽

Globin Gene ◽

Beta Globin ◽

Nerve Growth ◽

Transcriptional Induction

Nerve growth factor (NGF) treatment of PC12 cells leads to the elaboration of a neuronal phenotype, including the induction of neuronally expressed genes such as vgf. To study vgf transcription, we have created chimeric vgf/beta-globin genes in which vgf promoter sequences drive the expression of the beta-globin reporter gene or of a chimeric beta-globin gene fused to 3' untranslated vgf gene sequences. We have found that the level of inducibility of the latter construct by NGF resembles that of the endogenous vgf gene. Using transient transfection of the chimeric reporter genes into PC12 cells, into PC12 subclones expressing activated or dominantly interfering mutant Ras proteins, and into PC12 variants expressing specific NGF receptor/Trk mutants, we show that transcriptional regulation of the vgf promoter by NGF is mediated through a Ras-dependent signaling pathway. By mutational analysis of the vgf promoter, we have identified three promoter elements involved in mediating transcriptional induction by NGF and Ras. In addition to the cyclic AMP-responsive element (CRE), which binds to ATF-1, ATF-2, and CRE-binding protein in PC12 nuclear extracts, a novel CCAAT element and its binding proteins were identified, which, like the CRE, is necessary but not sufficient for the Ras-dependent induction of the vgf gene by NGF. We also identify a G(S)G element unusually located between the TATA box and transcriptional start site, which binds the NGF- and Ras-induced transcription factor, NGFI-A, and amplifies the transcriptional response. Integrating data from studies of vgf promoter regulation and NGF signal transduction, we present a model for vgf gene induction in which transcriptional activation is achieved through the persistent, direct activation of multiple interacting transcription factors binding to CRE and CCAAT elements, coordinated with the delayed transcription factor action at a G(S)G element resulting from the induced expression of NGFI-A.

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