Regulation of GPCR Anterograde Trafficking by Molecular Chaperones and Motifs

Young, Brent; Wertman, Jaime; Dupré, Denis J.

doi:10.1016/bs.pmbts.2015.02.012

Cited by 11 publications

(7 citation statements)

References 91 publications

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“…GPCR export from the ER, the first organelle in the secretory pathway, is a dynamic and highly regulated event in the biogenesis of GPCRs . Several endoplasmic reticulum (ER) exit motifs ‐ diacidic, dibasic and dihydrophobic sequences ‐ in the C‐terminus) of many GPCRs appear to contribute to efficient ER trafficking . The C‐terminus of A 2a R has been shown to contain various ER exit motifs .…”

Section: Resultsmentioning

confidence: 99%

The A_2aR C‐terminus provides improved total and active expression yields for adenosine receptor chimeras

2018

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Heterologous expression of many G‐protein coupled receptors (GPCRs) is a major bottleneck in drug discovery efforts for therapeutic development of the receptor. The goal of this study was to utilize domains from a well‐trafficked GPCR to aid in improving the trafficking of a related receptor. The adenosine A2a receptor (A2aR) shows exceptional expression and trafficking to the plasma membrane in yeast; however, this is not the case for other adenosine receptors. A2aR has a longer C‐terminus than the other adenosine receptors, which may contribute to its exceptional trafficking to the plasma membrane. To test the possibility to improve trafficking of the adenosine A1 receptor (A1R), chimeric receptors containing the seven transmembrane domains of A1R and the full‐length or truncated A2aR C‐terminus were constructed. The chimeric receptor showed improved localization to the plasma membrane and was capable of binding radioligand with native A1R affinity. Functionally active A1R receptor variants were produced at a theoretical yield of 95 pmol/mg total membrane protein, estimated using radioligand binding data, which are greater than three‐fold higher than previously reported yields from other heterologous expression systems, and should facilitate biophysical characterization and drug discovery efforts. © 2018 American Institute of Chemical Engineers AIChE J, 64: 4297–4307, 2018

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Section: Resultsmentioning

confidence: 99%

The A_2aR C‐terminus provides improved total and active expression yields for adenosine receptor chimeras

2018

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“…Homer proteins interact with the proline-rich motif of the C-terminus of group I metabotropic glutamate receptors (mGluRs) 1 and 5 [ 131 ]. In this way, Homer proteins modulate the expression and localization of mGluR1a and mGluR5.…”

Section: Signaling Within Complexes Of Gpcrs With Other Protein CLmentioning

confidence: 99%

Signaling within Allosteric Machines: Signal Transmission Pathways Inside G Protein-Coupled Receptors

2017

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In recent years, our understanding of function of G protein-coupled receptors (GPCRs) has changed from a picture of simple signal relays, transmitting only a particular signal to a particular G protein heterotrimer, to versatile machines, capable of various responses to different stimuli and being modulated by various factors. Some recent reports provide not only the data on ligands/modulators and resultant signals induced by them, but also deeper insights into exact pathways of signal migration and mechanisms of signal transmission through receptor structure. Combination of these computational and experimental data sheds more light on underlying mechanisms of signal transmission and signaling bias in GPCRs. In this review we focus on available clues on allosteric pathways responsible for complex signal processing within GPCRs structures, with particular emphasis on linking compatible in silico- and in vitro-derived data on the most probable allosteric connections.

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“…Like all membrane proteins, GPCRs are synthesized, folded, and assembled at the endoplasmic reticulum (ER), from where they migrate to the ER–Golgi intermediate complex, the Golgi apparatus and the trans-Golgi network, and finally to the PM [ 88 ]. During this process, they may form dimers or multimers with their partner GPCRs or themselves and with GIPs and acquire post-translational modifications such as glycosylation [ 88 ]. In some cases, dimerization is essential for transport and PM localization, hence the partner GPCR can be considered a chaperone as well.…”

Section: Regulation Of Sweet Taste Signalingmentioning

confidence: 99%

“…The failure to localize to the plasma membrane was an early hurdle to their functional expression in heterologous systems, which was only solved after identifying a suitable chaperone GIP. The major types of GIPs involved in anterograde transport include the homer proteins, small GTPases, receptor activity-modifying protein (RAMP), receptor-transporting protein (RTP), and receptor expression-enhancing protein (REEP) family members [ 88 ]. So far, the only GIP known to regulate STR localization to the PM is REEP2 [ 90 ].…”

Section: Regulation Of Sweet Taste Signalingmentioning

confidence: 99%

Sweet Taste Signaling: The Core Pathways and Regulatory Mechanisms

Sukumaran

Palayyan

2022

IJMS

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Sweet taste, a proxy for sugar-derived calories, is an important driver of food intake, and animals have evolved robust molecular and cellular machinery for sweet taste signaling. The overconsumption of sugar-derived calories is a major driver of obesity and other metabolic diseases. A fine-grained appreciation of the dynamic regulation of sweet taste signaling mechanisms will be required for designing novel noncaloric sweeteners with better hedonic and metabolic profiles and improved consumer acceptance. Sweet taste receptor cells express at least two signaling pathways, one mediated by a heterodimeric G-protein coupled receptor encoded by taste 1 receptor members 2 and 3 (TAS1R2 + TAS1R3) genes and another by glucose transporters and the ATP-gated potassium (KATP) channel. Despite these important discoveries, we do not fully understand the mechanisms regulating sweet taste signaling. We will introduce the core components of the above sweet taste signaling pathways and the rationale for having multiple pathways for detecting sweet tastants. We will then highlight the roles of key regulators of the sweet taste signaling pathways, including downstream signal transduction pathway components expressed in sweet taste receptor cells and hormones and other signaling molecules such as leptin and endocannabinoids.

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Regulation of GPCR Anterograde Trafficking by Molecular Chaperones and Motifs

Cited by 11 publications

References 91 publications

The A_2aR C‐terminus provides improved total and active expression yields for adenosine receptor chimeras

The A_2aR C‐terminus provides improved total and active expression yields for adenosine receptor chimeras

Signaling within Allosteric Machines: Signal Transmission Pathways Inside G Protein-Coupled Receptors

Sweet Taste Signaling: The Core Pathways and Regulatory Mechanisms

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Regulation of GPCR Anterograde Trafficking by Molecular Chaperones and Motifs

Cited by 11 publications

References 91 publications

The A2aR C‐terminus provides improved total and active expression yields for adenosine receptor chimeras

The A2aR C‐terminus provides improved total and active expression yields for adenosine receptor chimeras

Signaling within Allosteric Machines: Signal Transmission Pathways Inside G Protein-Coupled Receptors

Sweet Taste Signaling: The Core Pathways and Regulatory Mechanisms

Contact Info

Product

Resources

About

The A_2aR C‐terminus provides improved total and active expression yields for adenosine receptor chimeras

The A_2aR C‐terminus provides improved total and active expression yields for adenosine receptor chimeras