Elsevier

Cellular Signalling

Volume 18, Issue 10, October 2006, Pages 1549-1559
Cellular Signalling

Review
Biosynthesis and trafficking of seven transmembrane receptor signalling complexes

https://doi.org/10.1016/j.cellsig.2006.03.009Get rights and content

Abstract

Recent studies have shown that 7-transmembrane receptors (7TM-Rs), their associated signalling molecules and scaffolding proteins are often constitutively associated under basal conditions. These studies highlight that receptor ontogeny and trafficking are likely to play key roles in the determination of both signalling specificity and efficacy. This review highlights information about how 7TM-Rs and their associated signalling molecules are trafficked to the cell surface as well as other intracellular destinations.

Introduction

As the single largest family of cell-surface receptors, 7TM-Rs recognize a vast diversity of cellular modulators, including hormones, neurotransmitters, lipids, nucleotides, peptides, ions, and photons [1]. In addition to being activated by agonists that bind to receptors, 7TM-R signalling systems also demonstrate spontaneous, ligand-independent activation. It has also been shown that certain genetic mutations in genes coding for these proteins can result in increased agonist-independent, constitutive signalling which results in diseases such as precocious male puberty [2], retinitis pigmentosum [3] and thyroid adenomas [4]. 7TM-R signal transduction systems also constitute the largest class of drug targets for the therapeutic treatment of diseases. More than 50% of currently marketed prescription drugs directly or indirectly target these systems, accounting for more than US$20 billion of annual sales worldwide. Furthermore, the potential for additional therapeutic strategies that target these systems is considerable; currently available drugs target pathways that are controlled by only 10% of the 400 non-olfactory human 7TM-Rs (of approximately 800 in total) that have been identified thus far [5], [6].

Section snippets

Signalling via 7TM-Rs

Upon receptor activation, various signalling systems are activated leading to the regulation of diverse effector proteins such as enzymes and/or ion channels by an intermediate transducer. The most common transducers are heterotrimeric GTP-binding proteins (G proteins), composed of α, β and γ subunits. There are human genes for 15 Gα, 5 Gβ and 11 Gγ subunits (http://www.ncbi.nlm.nih.gov/genome/guide/human/), as well as a number of splice variants [7]. Several reports have also revealed that

Receptor oligomerization

A growing body of biochemical and biophysical evidence suggests that most 7TM-Rs can form homo- and/or hetero-oligomeric complexes [22], [23], [24], [25], [26], [27], [28], [29], [30]. Although their existence is now largely accepted, their functional importance still remains unclear and in many cases controversial [31], [32]. While 7TM-R biosynthesis and transport towards cell surface remain poorly characterized in general, their exit from the endoplasmic reticulum (ER) has been defined as a

Rab GTPases

The translocation of proteins between cellular compartments is a rapid, tightly regulated, and highly specific process (Fig. 1). Among the proteins that appear to regulate these movements are a family of Ras-related GTPases known as Rabs (see [113], [114], [115], [116] for review). Briefly, Rab GTPases were discovered during a screen for cDNAs encoding ras-related proteins [117] and were found to be similar to those of the yeast proteins Ypt1 and Sec4p, both of which were known to be required

Hints from other receptor and ion channel systems

In neurons, Rab8 has an exclusive somatodendritic distribution while in epithelial and photoreceptor cells, it mediates the transport between the trans-Golgi network and the plasma membrane [124], [166], [167], [168]. Using quantitative surface immunostaining, Gerges et al. showed that Rab8 is required for the delivery of AMPA-type glutamatergic receptors (AMPARs) to the spine surface, but not for transport of AMPARs from the dendritic shaft into the spine compartment or for AMPAR delivery into

Larger signalling complexes and trafficking: direction unknown

There is now significant evidence that signalling complexes form during biosynthesis and are assembled before targeting to the plasma membrane. It is becoming clear that 7TM-Rs interact constitutively and stably with their G protein partners and effectors ([181], [182], see [164] for review but also [183] for a contrary viewpoint). Where these initial interactions occur remains unclear a role for the composition of a specific signalling complex in determining its trafficking itinerary must be

Acknowledgements

We apologize to numerous colleagues whose work could not be cited due to space constraints. T.E.H. is a MacDonald Scholar of the Heart and Stroke Foundation of Canada and holds a senior scholarship from the Fond de Recherche en Santé du Québec. D.J.D. holds a postdoctoral fellowship from the Heart and Stroke Foundation of Canada. We thank Victor Rebois for helpful discussions especially with regard to Table 1. Raphaëlle Dupré and Madeleine Hébert are also acknowledged by D.J.D. and T.E.H. for

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