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Spatial Programming of G Protein-Coupled Receptor Activity 1 MINI-REVIEW 2 Spatial programming of G protein-coupled receptor activity: 3 decoding signalling in health and disease 4 Camilla West and Aylin C. Hanyaloglu* 5 Institute of Reproductive Biology and Development, Department of Surgery and Cancer, Imperial 6 College London, UK 7 8 *Corresponding author and to whom reprint requests should be addressed: Dr. Aylin 9 Hanyaloglu, Institute of Reproductive and Developmental Biology, Rm 2006, Department of 10 Surgery and Cancer, Imperial College London, London, W12 0NN, UK 11 Tel: +44(0)20 759 42128 12 Email: [email protected] 13 Abbreviated Title: Spatial control of GPCR signaling 14 Key words: G protein-coupled receptor, trafficking, signaling, microdomain, endosome, 15 reproduction. 16 17 Word Count: 5387 18 Number of Figures: 1 19 20 Disclosure Statement: The authors have nothing to disclose 1 21 ABSTRACT 22 Probing the multiplicity of hormone signaling via G protein-coupled receptors (GPCRs) has 23 demonstrated the complex signal pathways that underlie the multiple functions these receptors play in 24 vivo. This is highly pertinent for the GPCRs key in reproduction and pregnancy that are exposed to 25 cyclical and dynamic changes in their extracellular milieu. How such functional pleiotropy in GPCR 26 signaling is translated to specific downstream cellular responses, however, is largely unknown. 27 Emerging data strongly supports mechanisms for a central role of receptor location in signal 28 regulation, via membrane trafficking. In this review, we discuss current progress in our understanding 29 of the role membrane trafficking plays in location control of GPCR signaling, from organized plasma 30 membrane signaling microdomains, potentially provided by both distinct endocytic and exocytic 31 pathways, to more recent evidence for spatial control within the endomembrane system. Application 32 of these emerging mechanisms in their relevance to GPCR activity in physiological and 33 pathophysiological conditions will also be discussed, and in improving therapeutic strategies that 34 exploits these mechanisms in order to program highly regulated and distinct signaling profiles. 2 35 INTRODUCTION 36 Within any cellular signaling system it is becoming apparent that signal location is a critical 37 mechanism for cells to translate complex signaling networks at a spatial and temporal level, into 38 specific downstream responses. The membrane trafficking of receptors and the signaling molecules 39 they activate, can direct the location of intracellular signals, and has such been viewed as an 40 integrated cross-regulatory cellular system (1). Thus, membrane trafficking can regulate many 41 fundamental cellular programs and an increasing number of clinical conditions have been reported to 42 result from defects in membrane trafficking pathways or cargo sorting (1,2). The role of location in 43 signal regulation via membrane trafficking is highly pertinent for the signaling activated by the 44 superfamily of G protein-coupled receptors (GPCRs). A well-established contribution that trafficking 45 plays in GPCR signaling is the ability to regulate heterotrimeric G protein signal patterns (3). A 46 simple but dramatic example is the divergent sorting of GPCRs following ligand-induced endocytosis 47 to either recycling or degradative/lysosomal pathways (see Figure 1) a process that essentially 48 produces opposite effects on receptor signaling via its cognate G proteins (3). Furthermore, the 49 potential to reprogram signaling by altering trafficking or location of receptors may be a key adaptive 50 mechanism for GPCRs that are exposed to cyclical and dynamic hormonal environments, such as 51 those receptors central to regulating reproduction and pregnancy. In this review, we will highlight the 52 recent advances in our understanding that membrane trafficking plays in location control of GPCR 53 signaling, focusing where possible, on reproductive-relevant GPCRs, and the potential therapeutic 54 application and exploitation of these findings. 55 CLATHRIN-COATED PITS-MORE THAN JUST A MODE OF ENDOCYTOSIS? 56 The removal of GPCRs from the cell surface, via the process of endocytosis, is well established to 57 regulate receptor signaling by contributing to heterotrimeric G protein-signal desensitzation. Several 58 pathways have been described to regulate receptor-mediated endocytosis, however, clathrin-mediated 59 endocytosis (CME) via clathrin-coated pits (CCPs) is the most extensively characterized. CCPs are 60 formed by the recruitment and ordering of clathrin coat proteins with cargo, accessory proteins and 3 61 adaptors (Figure 1, B, reviewed in (4,5)). A new vesicle is then formed following the scission of the 62 CCP from the membrane by the dynamin family of GTPases (6). The widely accepted model for 63 GPCR recruitment to CCPs is that a ligand-activated receptor is first phosphorylated (by a member of 64 the family of the GPCR kinases (GRKs)), which increases the affinity of the cytoplasmic adaptor 65 proteins arrestin 2 and/or 3 to the receptor. Arrestins have the ability to bind clathrin heavy chain, 66 beta(2)adaptin subunit of the clathrin adaptor AP2 and GPCRs, thus facilitating GPCR recruitment 67 and clustering into CCPs for their subsequent internalization (reviewed in (7)). In addition to 68 uncoupling heterotrimeric G protein signaling from the plasma membrane, arrestins also directly 69 activate GPCR signaling independent of their cognate G proteins, by acting as scaffolds for a variety 70 of signaling proteins (Figure 1, C). Distinct GPCRs can vary in how they engage in receptor-mediated 71 endocytosis including; preferential arrestin recruitment, phosphorylation via distinct kinases, ligand- 72 independent internalization and even arrestin- and/or clathrin-independent internalization. This has 73 been extensively reviewed elsewhere (8-11). Instead we will focus on how these pathways, machinery 74 and distinct clathrin-containing plasma membrane domains may enable tight control of cell surface 75 organization as a mechanism to exquisitely regulate cell signaling. 76 77 The diverse range of cargo and machinery reported to assemble to CCPs has raised the question of 78 whether there is heterogeneity in localization across CCPs for different receptors, and in turn whether 79 this impacts subsequent sorting and signal activity of a receptor. That distinct receptors may be 80 organized within distinct subsets of CCPs was first reported for the β2-adrenergic receptor (β2AR) 81 (12). A role for such specialized spatial organization of CCPs was then demonstrated to dictate its 82 subsequent sorting to recycling or lysosomal pathways (13), as also shown for the purinergic 83 receptors, P2Y(1) and P2Y(12), that identified two distinct CCP populations (14,15) also with 84 functional implications in differential post-endocytic sorting. Mechanistically, the targeting of 85 receptors to these distinct CCPs was dependent on arrestin and phosphorylation, with P2Y(12) and 86 β2ARs recruited in an arrestin and GRK-dependent manner and P2Y(1) in an arrestin-independent yet 87 PKC-dependent manner. An additional GPCR well known to internalize via an arrestin-independent 4 88 manner is the mammalian gonadotropin-releasing hormone receptor (GnRHR (16). Although reported 89 to localize to clathrin and caveolae/lipid rafts depending on the cell type (see below), this receptor 90 rapidly recycles following ligand-induced internalization (17), unlike the arrestin-independent 91 P2Y(1), so it is possible there may be further subspecializations of CCPs that is dictated by 92 associating adaptor molecules. The impact of such subspecialization on receptor activity, and 93 consequently its downstream physiological function, may be to function as ‘bona fide’ signalling 94 microdomains, e.g. via arrestin-dependent signal complexes (Figure 1, C). The potential role of CCPs 95 to act as signaling microdomains is highlighted by the ability of GPCRs to regulate their own CCP 96 residency time. For the β2AR this is achieved by interaction with additional protein scaffold proteins, 97 namely postsynaptic density 95/disc large/zonula occludens-1 (PDZ) proteins, that tether GPCRs to 98 cortical actin, and extend the occupancy time of a receptor in a CCP by delaying the recruitment of 99 dynamin (15). However, other receptors such as the mu-opioid receptor delay the scission activity 100 rather than recruitment of dynamin, and in a PDZ-independent manner (18). Functionally delayed 101 residency time of a GPCR in CCPs provides a mechanism to regulate mitogenic signals on a temporal 102 scale via formation of arrestin signaling scaffolds, as suggested by a recent study measuring residency 103 times with distinct agonists of the cannabinoid CB1 receptor (19). The CB1 cannabinoid receptor, as 104 part of the endocanabinoid system, modulates synaptic function, including negative regulation of 105 GABAergic input to GnRH neurons, suppressing GnRH output and fertility (20) and thus such spatio- 106 temporal regulation of CB1 signaling may be key in its role in modulating release of GABA from the 107 presynaptic membrane under physiological or pathophysiological conditions, e.g. the ability of 108 cannabis drugs to inhibit pituitary LH secretion. Additional downstream cellular consequences for 109 tight spatial control of GPCR signalling, such as that generated from CCPs, has been recently 110 demonstrated between PAR2 and neurokinin1 (NK1) receptor whose arrestin-dependent ERK 111 signaling mediates either cell
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