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Endocrinology Vol. 145, No. 8 3590-3593
Copyright © 2004 by The Endocrine Society

Outside-In and Inside-Out Signaling: The New Concept that Selectivity of Ligand Binding at the Gonadotropin-Releasing Hormone Receptor Is Modulated by the Intracellular Environment

Robert P. Millar and Adam J. Pawson

Medical Research Council Human Reproductive Sciences Unit, Edinburgh EH16 4SB, Scotland, United Kingdom

Address all correspondence and requests for reprints to: Prof. Robert P. Millar, Medical Research Council Human Reproductive Sciences Unit, Centre for Reproductive Biology, The University of Edinburgh Chancellor’s Building, 49 Little France Crescent, Edinburgh EH16 4SB, Scotland, United Kingdom. E-mail: r.millar{at}hrsu.mrc.ac.uk.

The classical view of receptor theory envisaged only two receptor states, active and inactive, and that agonists bind and stabilize the active state to increase intracellular signaling. However, many experimental findings were inconsistent with this concept and suggested that different agonists could stabilize different receptor active states, which in turn would selectively stimulate different signaling pathways. This concept was proposed almost a decade ago by Kenakin (1) and dubbed "agonist trafficking of receptor signals." Since then, substantial experimental data and theoretical consideration have supported the concept that receptors oscillate between numerous conformations, some of which are selective for certain agonists and signaling pathways (reviewed in Ref. 2). This means that the "flavor" of ligand binding and signaling is determined by specific receptor conformations (Fig. 1Go). It is important to recognize in this concept that there is a bidirectional relationship in the molecular cascade. Thus, specific ligand (L1) will selectively bind a particular receptor conformation (R1), which in turn will activate particular signaling protein complexes (SC1). Conversely, signaling complex (SC1) will stabilize receptor conformation (R1) that will selectively bind ligand (L1). Direct evidence for the existence of multiple conformations of a G protein-coupled receptor (GPCR) was provided by the technique of fluorescence lifetime spectroscopy of the ß2-adrenoceptor covalently tagged with a fluorescent probe (3). It is difficult to envisage any intermolecular interaction that would not influence microconformational change in the binding partners involved. Therefore, we should anticipate that the specific nature of the intracellular protein complexes will selectively stabilize certain receptor conformations. This will therefore depend on the cell type and its recent history (e.g. prior activation of the same or different receptor, exposure to steroid hormones, etc.).



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  		FIG. 1. Schematic of the concept of multiple active states (conformers) of a single receptor (R1–R4) that are selective for different agonist analogs (L1–L4). The different active receptor conformers are selectively coupled to different signaling complexes (SC1–SC4) that give rise to different effects in cells. Kenakin’s "agonist trafficking of receptor signals" envisages that a specific agonist (e.g. L1) will selectively bind and stabilize the active receptor conformer (R1), which will activate signaling complex (SC1). In the presence of L1 and the absence of other agonists, more of R1 will be stabilized and more SC1 is recruited and activated (shown in bold black). It also follows that the presence of more SC1 (e.g. a specific cell type, or prior homologous or heterologous receptor activation resulting in phosphorylation, etc.) will stabilize more of active receptor conformer R1 and increased binding of R1-selective agonist L1.

 
Clearly, this greatly enlarges the possibility of developing highly specific drugs targeting specific cells and tissues, but it also considerably complicates the process of drug discovery. In addition, it alerts us to limitations in extrapolating data derived from clonal cell lines to cells in living organisms.

In this issue of Endocrinology, McArdle and colleagues (4) have provided a seminal example of the effects of modifying the intracellular environment on the binding selectivity of a Xenopus GnRH receptor. Activation of protein kinase C (PKC) led to a marked increase in [125I]GnRH II binding to the Xenopus type I receptor (not type II as stated; see Refs. 5, 6, 7) but had no effect on binding of a [125I]GnRH I agonist (Buserelin) to the human and sheep type I GnRH receptors. The mammalian type I GnRH receptors are unique among GPCRs in lacking a carboxyl-terminal tail and exhibit prolonged GnRH-stimulated signaling (8, 9, 10, 11, 12). This prompted McArdle’s group to study human and sheep receptors with the addition of the Xenopus receptor carboxyl-terminal tail. Both constructs showed a marked increase in binding of [125I]GnRH II and no change in [125I]GnRH I agonist binding after PKC activation with a phorbol ester. These findings strongly suggest that PKC phosphorylation of intracellular proteins in HeLa cells results in the stabilization of a GnRH receptor conformation that is selective for GnRH II. The findings further indicate that the carboxyl-terminal tail of the Xenopus receptor is necessary for the phenomenon, and suggest that phosphorylation of the tail may be involved in increasing GnRH II binding. Mutation of two putative phosphorylation sites did not ablate the effect. However, there are another 11 serine/threonines (5, 7), one of which is a PKC site, so this does not exclude the possibility that the tail is phosphorylated. If, however, tail phosphorylation is not involved, an alternative mechanism is the phosphorylation of intracellular proteins that themselves associate with the carboxyl-terminal tail or induce other proteins to do so, thereby preferentially stabilizing receptor conformations selective for GnRH II.

The effects of intracellular modulation on GnRH receptor ligand pharmacology was in fact suggested many years ago by early studies on GnRH analog binding studies and by antiproliferative effects of GnRH analogs on reproductive tract tumor cell lines. The binding affinity of conventional GnRH agonists was much lower in these tumors and cell lines than in the pituitary (13, 14, 15). Moreover, GnRH agonists and certain antagonists had similar antiproliferative effects on tumor cell lines (Refs. 14 and 16 ; see Refs. 17, 18, 19, 20 for reviews). Similar GnRH binding sites have been found in placenta, gonads, uterus, and prostate (see Ref. 15 for review). These findings suggested the existence of a different GnRH receptor in these cells and tissues. The search for a type II GnRH receptor led to the identification of a putative novel receptor in human databases (21, 22, 23) and the cloning of a full-length transcript in the bullfrog (24). Full-length functional type II GnRH receptors were then cloned from the marmoset (25) and green and rhesus monkeys (26). These receptors exhibited pharmacology similar to that seen in tumor cells (e.g. certain antagonists behaved as agonists) (25), and their discovery seemed to answer all of the questions. However, the human homolog turned out to have a frameshift and stop codon that would not accommodate translation into a full-length functional GPCR (27). This paradox has recently been resolved by demonstrating that the classical human type I GnRH receptor can exhibit the abnormal pharmacology (i.e. different from that seen in pituitary cells) when expressed in HEK 293, benign prostatic hyperplasia (BPH-1), and choriocarcinoma (JEG-3) cells (7). From this has emerged the concept that the intracellular environment can modulate the ligand-binding characteristics of the GnRH receptor and the nature of the intracellular signaling elicited by the analogs (7). The logical extension of this realization is that certain GnRH analogs will selectively bind specific active conformations of the GnRH receptor that are stabilized by specific intracellular protein complexes, which will also convey the "flavor" of the signaling of the specific ligand. We have referred to this phenomenon as ligand-selective signaling (7). Perhaps the best example is a GnRH analog (135-25) that is an antagonist at inhibiting Gq activation by the type I GnRH receptor in pituitary cells but is a full agonist in antiproliferative effects on tumor cells (through Gi activation). The two GnRH ligands that occur in man (GnRH I and GnRH II) also show distinctively different pharmacology for Gq and Gi at the human type I receptor when expressed in pituitary gonadotropes or tumor cells. A simple depiction is shown in Table 1Go.


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  		TABLE 1. Differential signaling of GnRH analogs

 
The ability of the intracellular protein complexes to stabilize different conformations of the GnRH receptor presumes that there is intimate contact of the protein complexes with the GnRH receptor. The classical view of signal transduction processes involves signaling intermediates that can reach their targets either by diffusion through the cytosol or within the plasma membrane. However, in many cases, these signaling intermediates are preassembled on molecular scaffolds such as the postsynaptic density protein-95, discs-large, zonula occludens-1 (PDZ) domain family of scaffold molecules, which recognize three classes of PDZ domain-binding motifs located at the carboxyl terminus of target proteins (28). Such scaffolds link several components of a signaling pathway to the signaling receptor, thereby increasing the specificity and rate of signal transduction. The nature of the scaffold components is determined by the cellular protein complement and local concentration of signaling intermediates in compartmentalized membrane microdomains. Such microdomains include lipid rafts and caveolae that act to organize and concentrate receptors and cognate signaling components into discrete membrane domains, thereby imparting specificity to extracellular stimuli. Conversely, scaffolding of GPCRs in compartmentalized membrane microdomains probably also stabilizes different receptor conformations, thus imparting ligand specificity at the receptor. Thus, the nature of the preassembled receptor-signaling scaffold complex would determine the nature of the preferred ligand, by stabilizing a particular receptor conformation. Activation of the receptor by binding the preferred ligand would then induce a different receptor active conformation that would preferentially recruit different signaling complex components, to the preassembled scaffold, to ultimately determine the route of signal transduction. Studies in our laboratory and others have demonstrated that GnRH receptors constitutively localize to lipid rafts in a gonadotrope cell line ({alpha}T3-1) (29) and HEK 293 cells stably expressing the rat GnRH receptor (our unpublished data). The Rho family of small GTPases, RhoA and Rac1 are thought to be concentrated in lipid rafts and caveolae. Rac1, whose translocation to the plasma membrane is regulated by GPCR signaling (including GnRH receptor) via integrin-mediated focal adhesion-based scaffolding complexes leading to actin cytoskeleton remodeling and MAPK cascade activation (30), has been shown to bind preferentially to lipid rafts (31). Furthermore, we have recently demonstrated that GnRH receptors signal and undergo internalization in lipid rafts/caveolae microdomains (32).

We have observed a putative class II PDZ-domain binding motif (Tyr-Phe-Ser-Leu-COOH) at the carboxyl terminus ofthe human GnRH receptor (and indeed all of the mammalian type I GnRH receptors), which may allow interaction with PDZ domain-based signaling scaffold complexes (7, 33). It is interesting to note that the Xenopus GnRH receptor used in the study by McArdle and colleagues has a carboxyl-terminal class I PDZ-domain binding motif (Gln-Ser-Val-Phe-COOH). The McArdle group demonstrated reliance on the presence of the carboxyl-terminal tail of the Xenopus GnRH receptor for the observed pharmacology. This raises the interesting possibility that complexing with PDZ domain signaling scaffolds is the determinant for the preferential GnRH II selectivity that was observed. Certainly, the actions of many PDZ domain scaffold molecules are modulated by particular second messengers and kinases, such as PKC activation [e.g. protein interacting with C-kinase (PICK-1)] (28).

The article by McArdle and colleagues is groundbreaking in demonstrating a particular modulation of the intracellular environment (viz. PKC phosphorylation of proteins) that affects GnRH receptor ligand selectivity. As is often the case, it also raises many unanswered questions. Is the Xenopus tail phosphorylated or not? What are the proteins that associate with the receptor to affect ligand selectivity? Only receptors with the Xenopus tail exhibit the phenomenon, yet we know that similar changes in pharmacology are seen in the human receptor in different cell backgrounds [e.g. GnRH II is much less potent than GnRH I at the gonadotrope (Gq) but much more potent in tumor cells (Gi)]. What protein complexes are mediating the changed pharmacology of the human GnRH receptor in these backgrounds?

The GnRH receptor field is evidently entering a new exciting era that is likely to usher in novel signal-selective GnRH analog therapeutics.


   Footnotes
 
Abbreviations: GPCR, G protein-coupled receptor; L, ligand; PDZ, postsynaptic density protein-95, discs-large, zonula occludens-1; PKC, protein kinase C; R, receptor conformation; SC, signaling complex.

Received April 9, 2004.

Accepted for publication April 13, 2004.


   References
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