GPCR signalling to the translation machinery

doi:10.1016/j.cellsig.2009.10.012

Cellular Signalling

Volume 22, Issue 5, May 2010, Pages 707-716

https://doi.org/10.1016/j.cellsig.2009.10.012 Get rights and content

Abstract

G protein-coupled receptors (GPCRs) are involved in most physiological processes, many of them being engaged in fully differentiated cells. These receptors couple to transducers of their own, primarily G proteins and β-arrestins, which launch intracellular signalling cascades. Some of these signalling events regulate the translational machinery to fine-tune general cell metabolism or to alter protein expression pattern. Though extensively documented for tyrosine kinase receptors, translational regulation by GPCRs is still poorly appreciated. The objective of this review paper is to address the following questions: i) is there a “GPCR signature” impacting on the translational machinery, and ultimately on the type of mRNA translated? ii) are the regulatory networks involved similar as those utilized by tyrosine kinase receptors? In particular, we will discuss the specific features of translational control mediated by GPCRs and highlight the intrinsic properties of GPCRs these mechanisms could rely on.

Introduction

G protein-coupled receptors (GPCRs) are the largest class of integral membrane receptors involved in signal transduction from the cell environment inward. Their cognate ligands encompass a vast array of structural entities, including glycoprotein hormones, chemokines, peptide neurotransmitters, ions, as well as sensory molecules such as light, odorants or taste ligands. As one can tell from this plethora of ligands, GPCRs are involved in key physiological processes, making them one of the top target classes for pharmaceuticals. Although many of these responses occur in fully differentiated cells [1], the role of GPCRs in transducing mitogenic responses has also been appreciated [2], [3]. It is now well established that GPCRs and tyrosine kinase receptors (TKRs) share common signalling pathways, to stimulate mitogenic responses as well as neosynthesis of differentiation markers. That is, both types of receptors couple to adaptor proteins of their own, whereby they both launch intracellular phosphorylation cascades. Many of these signalling events regulate gene expression transcriptionally, whereas some others input on the translational machinery. Protein synthesis is critical for cell growth and development, and its deregulation is implicated in diseases, such as Alzheimer disease or in tumorigenesis [4]. Beside maintenance of cell homeostasis, changes in the rate of mRNA translation arise when environmental conditions vary, so that the cell needs to fine-tune its protein content by both increasing the rate of overall translation and/or of only a subset of specific adaptative mRNA.

Translational regulation has been widely documented for TKRs [5], [6], but is still poorly appreciated for GPCRs. Several recent reports have suggested that the signalling mechanisms leading to translational regulation by both classes of receptors might be partly different, presumably leading to specific ultimate cell response. This is the topic of this review to discuss the main features of translational control mediated by GPCRs and to highlight the intrinsic properties of GPCRs these mechanisms could rely on. Bearing in mind the tremendous role of GPCRs in many if not all physiological responses of highly differentiated cells, the physiological relevance of GPCR-mediated translational control will also be discussed.

In the following, we have used the Cell Designer graphic interface (http://celldesigner.org), to formalize the topology of the signalling networks induced by different GPCRs. We tried to ignore the background knowledge whenever possible. Furthermore, only the signalling events involved in translational control and identified in the respective references are shown.

Section snippets

G protein-dependent transduction to the translational machinery

The classical scheme of GPCR signalling is that once bound to its cognate receptor, each ligand promotes conformational changes causing the physical association of the receptor with a GDP-bound G protein heterotrimer. The subsequent exchange of GDP for GTP on the Gα sub-unit releases the Gβγ dimer. Then, GTP-bound Gα on the one hand and Gβγ dimers on the other hand live their own life inside the cell to initiate independent, as well as intricate signalling events. Many GPCRs are preferentially

β-arrestin-dependent regulation of translation

An emerging notion which complexifies the classical view of GPCR transduction by heterotrimeric G proteins is that ligand binding induces a range of conformational changes that could overcome G coupling and lead to β-arrestin-mediated signalling. Initially known to convey GPCRs towards the endocytic machinery by virtue of their ability to bind the μ-adaptin subunit of the clathrin adaptor AP2 (adaptor protein 2) [77], [78], β-arrestins also support a temporal hierarchy of signalling events, by

The Odyssee of glutamate receptors

Dendritic protein neosynthesis via mTOR is critically involved in long-lasting, translation-dependent synaptic plasticity, occurring when synaptic connections are strengthened in long-term potentiation, as well as weakened in long-term depression (LTD) [96]. In the hippocampus, LTD can be mediated by Gq-coupled group I mGluRs (metabotropic glutamate receptors) [97], which enhance rpS6 phosphorylation and eEF1A neosynthesis [98], leading to increased mRNA translation [99] (Fig. 4). To understand

Concluding remarks

As summarized herein, a wide array of GPCRs enhance intracellular neosynthesis rate, once bound to their physiological agonist(s). The coupling of GPCR to Gα subtypes, such as Gα₀, Gα_12/13, Gα_t, Gα_z, has not been evoked here, because, to our knowledge, their role in translation has not been reported. At the cell membrane, only Gs- and Gq-coupled receptors utilize generic GPCR transducing mechanisms, such as second messenger production, to launch the initial signalling cascade. Within the cell,

Acknowledgements

The authors apologize to those whose work could not be cited here. They wish to thank Domitille Heitzler and Dr Vincent Piketty for critical reading of the manuscript. AM was funded by a fellowship of the Région Centre and of the Institut National de la Recherche Agronomique, France. BB was funded by the Institut National de la Recherche Agronomique. We thank the AEN INRA/INRIA REGATE for financial support.

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ReviewGPCR signalling to the translation machinery

Abstract

Introduction

Section snippets

G protein-dependent transduction to the translational machinery

β-arrestin-dependent regulation of translation

The Odyssee of glutamate receptors

Concluding remarks

Acknowledgements

J. Biol. Chem.

Trends Pharmacol. Sci.

J. Biol. Chem.

J. Biol. Chem.

FEBS Lett.

Cell

Mol. Cell

J. Biol. Chem.

Cell

J. Biol. Chem.

FEBS Lett.

J. Biol. Chem.

J. Biol. Chem.

Prostaglandins Other Lipid Mediat.

J. Biol. Chem.

Biochim. Biophys. Acta

J. Biol. Chem.

Mol. Cell. Endocrinol.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Cell

Cell. Signal.

J. Biol. Chem.

Biochim. Biophys. Acta

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Neuron

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Trends Endocrinol. Metab.

Cell

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Neuropharmacology

Wong Y.H.

Biofactors

Oncogene

J. Cell Physiol.

Biochem. J.

Nature

Nature

Mol. Endocrinol.

N. Engl. J. Med.

Biochem. J.

Review
GPCR signalling to the translation machinery