Identification and biological significance of G protein-coupled receptor associated sorting proteins (GASPs)

Abstract

G protein-coupled receptors (GPCRs) represent one of the most abundant protein families encoded by the human genome. They are involved in the modulation of numerous physiological functions and represent major drug targets. Their activity is tightly controlled by a vast array of interacting partners that modulate their membrane targeting, intracellular trafficking and signalling properties. Among them, several proteins from the same family, G protein-coupled receptor associated sorting proteins (GASP), have been shown to display a broad spectrum of interactions with GPCRs. In addition to their postulated role in the modulation of the post-endocytic sorting of these receptors, recent data indicate that several GASPs may modulate the transcriptional activity of the cell through their interaction with transcription factors. However, no clear molecular function has been assigned yet to this protein family. In this review, we describe the discovery of GASPs, their major features, interacting partners, functions and possible involvement in pathological situations including neurodegenerative diseases and cancer.

Introduction

G protein-coupled receptors (GPCRs) represent one of the most abundant protein families encoded by the human genome. By the most recent estimations there are a total of 799 sequence verified human GPCRs, of which 369 respond to endogenous ligands (see Lagerstrom & Schioth, 2008). These ligands display an extraordinary diversity, including amino acids, Ca²⁺ ions, peptides, lipid-like substances and large glycoprotein hormones. In animals, all physiological functions are modulated by complex equilibriums between different subsets of GPCRs. From a pharmaceutical point of view, these receptors are targeted by around 40% of all drugs available on the market (see Jacoby et al., 2006, Eglen et al., 2007). Noticeably, these compounds act through less than 50 different GPCRs leaving more than 300 receptors as potential targets for the development of therapeutic agents (see Lagerstrom & Schioth, 2008).

The activity of GPCRs is tightly regulated. Particularly, they interact with a vast repertoire of GPCR interacting proteins (GIPs) that display important functions, including the targeting of receptors to specific subcellular compartments, their trafficking to and from the plasma membrane and the fine-tuning of their signalling properties (see Bockaert et al., 2004). Consequently, if we want to discover and optimize new therapeutic agents targeting GPCRs we must appreciate the functioning of these novel interacting partners.

With the exception of arrestins, for which the interaction with numerous GPCRs has been largely demonstrated (see Pierce et al., 2002), most GIPs modulate the function of only one or a small subset of GPCRs. Some are transmembrane proteins while other are cyto-soluble and mainly interact with the C-terminal tail (C-tail) of receptors. In this review, we will describe the discovery and potential functions of a novel family of proteins, the so-called GPCR associated sorting proteins (GASPs). Like arrestins, they display a broad spectrum of interaction with GPCRs and may therefore represent an important family of proteins regulating GPCR physiology.