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Laitakari, A. The Zinc-Sensing Receptor GPR39. Encyclopedia. Available online: https://encyclopedia.pub/entry/9214 (accessed on 06 September 2024).
Laitakari A. The Zinc-Sensing Receptor GPR39. Encyclopedia. Available at: https://encyclopedia.pub/entry/9214. Accessed September 06, 2024.
Laitakari, Anna. "The Zinc-Sensing Receptor GPR39" Encyclopedia, https://encyclopedia.pub/entry/9214 (accessed September 06, 2024).
Laitakari, A. (2021, April 29). The Zinc-Sensing Receptor GPR39. In Encyclopedia. https://encyclopedia.pub/entry/9214
Laitakari, Anna. "The Zinc-Sensing Receptor GPR39." Encyclopedia. Web. 29 April, 2021.
The Zinc-Sensing Receptor GPR39
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This entry is adapted from the peer-reviewed paper 10.3390/ijms22083872

GPR39, also known as ZnR (zinc sensing receptor), is a member of a large family A of 7-transmembrane (7-TM) containing G protein-coupled receptors (GPCRs).

GPR39 GPR39 agonist zinc zinc signaling

1. Introduction

GPR39, also known as ZnR, is a member of a large family A of 7-transmembrane (7-TM) containing G protein-coupled receptors (GPCRs) [1]. GPR39 is found in all vertebrates and was cloned together with GPR38 as structural homologues to the ghrelin receptor from human fetal brain in 1997 [2] and belongs to the ghrelin receptor subfamily with six of its most closely related receptors [3]. The other members of this family are well-established regulators of metabolism through their ligands: the peptide hormones and neuropeptide regulators ghrelin, motilin, neurotensin and neuromedin U [3]. Conversely, no endogenous peptide ligand has been discovered for GPR39 [4]. Coincidentally, the existence of an ionic zinc (Zn2+) -sensing receptor was indicated in 2001, when extracellular Zn2+ was found to activate intracellular Ca2+ signaling; the receptor then named the Zn2+-sensing receptor (ZnR) and now known to be GPR39 [5]. Indeed, physiological concentrations of Zn2+ were shortly after shown to activate GPR39 [6][7][8].

Zinc is essential for human health and zinc deficiency is recognized as a world-wide malnutrition problem, affecting 17% of the global population [9]. All cell types require Zn2+ for various catalytic and regulatory functions and around 3000 proteins are estimated to have binding sites for Zn2+ [9][10]. Consequently, zinc deficiency affects the functions of multiple tissues and cell signaling pathways; for example, zinc plays a role in immune responses, DNA replication and repair, oxidative stress response, aging, cell cycle progression, homeostasis and apoptosis [9][11][12][13]. Extracellular Zn2+ concentration can increase in many circumstances, such as when Zn2+ is co-released from vesicles with insulin in the pancreatic β-cells or with glutamate in the nerve synapses, or in connection with cell death and injury, which then triggers GPR39-dependent signaling [14][15][16].

2. GPR39 Structure and Signaling

The gene encoding for GPR39 is located in the chromosome 2, locus q21.2, and is around 230 kb in size. The gene encoding the full-length 435 amino acid long (52 kD) GPR39-1 constitutes two exons, separated by an intron. The first exon consists of 285 amino acids and contains the transmembrane (TM) domains I–V and the second, consisting of 150 amino acids, the TM domains VI and VII. [2]. A truncated, 32 kD isoform containing the first five TM domains, GPR39-1b, has also been identified. This splice variant is likely to be inactive and does not dimerize with the full-length GPR39-1a, but has been shown to function as a dimerization partner to neurotensin receptor 1 (NTSR1), thus having a role as a negative regulator of NTSR1 signaling [17][18].

Upon ligand binding, GPCRs undergo conformational changes resulting in intracellular G-protein activation and subsequent downstream signaling [19]. GPR39 activation induces signaling pathways that regulate various cellular functions, such as survival, proliferation, differentiation, and ion transport [5][20][21][22] and has been shown to signal through Gαq, Gαs, Gα11/12 and β-arrestin recruitment [6][8][23][24]. When the downstream signaling upon GPR39 activation is mediated by Gαq, phospholipase C (PLCβ) is activated, resulting in inositol 1,4,5-triphosphate (InsP3) generation, which in turn stimulates Ca2+ release from its endoplasmic reticulum (ER) storages. The intracellular Ca2+ results in extracellular signal-regulated kinase (ERK1/2) and subsequent ERK/mitogen-activated protein kinase (MAPK) signaling pathway activation, and GPR39 activation also increases protein kinase B (AKT) phosphorylation and AKT/phosphoinositide 3-kinase (PI3K) signaling pathway activation [5][8][25][26][27]. These two pathways contribute to cell survival and proliferation, respectively [28][29]. Moderate cAMP response element (CRE)-mediated transcription induction is observed with GPR39 [6][8], mainly mediated by Gαs-induced cAMP production and protein kinase A (PKA) signaling [6]. GPR39 signaling is also able to induce Gα12/13 activation, which via PI3K and Ras homolog family member A (RhoA) induces serum response element (SRE)-mediated transcription [6][8]. GPR39 also triggers arrestin transport to the plasma membrane [6]. Recently, several studies have indicated GPR39 to interact with the NF-κB signaling pathway. However, all of these studies achieved their results by using a synthetic GPR39 agonist; thus, the question remains whether Zn2+ is able to activate this pathway in physiological conditions [30][31][32].

GPR39 has relatively high ligand-independent constitutive activity, based on an aromatic cluster on the inner face of the extracellular ends of TM domains VI and VII, similarly to other members of the ghrelin receptor family [8][33]. Gαq is the mediator of this, activating PLCβ, which results in an induction of InsP3 turnover. Activation of the ERK/MAPK pathway is not involved in the constitutive activity, which thus results only in modest CRE-mediated transcription induction. Constitutive GPR39 signaling was also able to induce Gα12/13 activation, and via PI3K and RhoA inducing robust serum response element (SRE)-mediated transcription [6][8]. The constitutive activity did not induce cAMP production, suggesting that Gαs is not involved [6]. However, a recent report suggested that the constitutive signaling of GPR39 varies between vertebrates. Whereas with human, chicken and frog the phylogenetic and selection analysis indicated Gαq and Gα11/12, zebrafish were shown to additionally constitutively activate Gαs [34]. The physiological roles of the constitutive activity are not clear, but it is important to note that due to it, variations in the expression of GPR39 also directly affect the potency of its downstream signaling.

A negative feedback method desensitizing GPR39 for further activation has been shown to take place and is important due to Zn2+ not being degraded like most ligands of GPCRs. A robust desensitization of GPR39 follows exposure to high concentrations of Zn2+, which can result in complete loss of GPR39 signaling dose- and time-dependently [14][24][35][36]. Internalization of membrane receptors into vesicles is a common method of desensitization for the GPCRs [37]. GPR39 was reported not to undergo basal internalization [8][38] and ZnCl2-induced internalization occurred at a significantly lower level compared to the ghrelin receptor in GPR39-overexpressing HEK293 cells [38]. However, GFP-tagged GPR39 was shown to internalize when stimulated simultaneously with Zn2+ and a GPR39 agonist TC-G 1008 [35]. The desensitization and internalization of GPR39 were shown to occur via Gα12/13 and RhoA [35], instead of internalization by β-arrestin, more typical to GPCRs [37].

GPR39 has been shown to be highly phosphorylated in basal conditions; the level of phosphorylation not further increased by Zn2+ [38]. Which kinase is responsible for this is still unknown, although one study suggested that G protein-coupled receptor kinase 2 (GRK2) might be involved [35].

GPCRs are known to form heteromeric complexes with other G proteins [39]. When GPR39 was co-expressed with the GPCRs 5-hydroxytriptamine 1A receptor (5-HT1A) and galanin receptor 1 (GalR1), GPR39 formed heterodimers with 5-HT1A and heterotrimers with both receptors in HEK-293S GnTi− cells [40]. The GPR39-5-HT1A complex was shown to increase SRE induction compared to GPR39 alone, suggesting that 5-HT1A might enhance GPR39 activity, but the presence of GalR1 blocked GPR39 signaling. Zn2+ was shown to modulate the interaction of GPR39 with the other receptors and to regulate the balance between receptor complex formation; at low Zn2+ concentrations the dominant complex was 5-HT1A-GalR1 and GPR39 was absent, whereas at higher Zn2+ concentrations, complexes with GPR39 were dominant [40]. Another extracellular cation sensing GPCR, the Ca2+ sensing receptor (CaSR), was suggested to interact and regulate GPR39 functionally when co-expressed in prostate cancer (PC3) or ductal salivary gland (HSY) cells [27]. GPR39 was shown to directly interact with CaSR by co-immunoprecipitation, and CaSR activity was shown to promote GPR39 surface expression and signaling, as treatment with a CaSR agonist increased the GPR39-dependent Ca2+ response [27]. Additionally, GPR39 has been suggested to interact with a calcium-activated anion channel, transmembrane member 16A (TMEM16A) [41]. GPR39 activation in primary intestinal fibroblast-like cells resulted in TMEM16A-dependent currents and membrane depolarization, suggesting that GPR39 activation is functionally linked to TMEM16A channel opening [41]. Additionally, the cAMP-dependent protein kinase A inhibitor β (PKIB) was identified as an interacting partner for GPR39 in a yeast-2-hybrid screen [42]. When co-expressed in Chinese hamster ovary cells, GPR39 co-localized with PKIB, resulting in an increase in its constitutive activity, but PKIB had no effect on the Zn2+-dependent activation of GPR39. Contrariwise, Zn2+ treatment resulted in a dissociation of PKIB from GPR39, switching the signaling from constitutive to ligand-dependent [42]. This suggests that Zn2+ is not only an agonist of GPR39, but also an important regulator of constitutive vs. ligand-dependent GPR39 signaling. In C2C12 myoblast cells, Pax7 has been shown to activate the transcription factor Zac1 in order to regulate GPR39 expression. GPR39 was suggested to be a direct target gene of Zac1 [43]. GPCR dimerization has been widely shown to affect their activity and affinity [39], which these studies suggest to be also accurate for GPR39. However, it is yet to be confirmed whether GPR39 oligomerization or the other interactions discussed here happen in physiological conditions, since most studies to date are performed in overexpression models in heterologous expression systems.

3. Ligands of GPR39

Initially, obestatin, a peptide encoded by the ghrelin gene, was suggested to be an endogenous ligand for GPR39, reducing food intake and gastric motility [23]. However, it was later confirmed that obestatin does not activate GPR39 [4][6].

3.1. Endogenous Ligands of GPR39: Zn2+

Zinc was first indicated to activate GPR39 in 2004 [8], and in 2007 two research groups showed that GPR39 senses changes in extracellular zinc concentrations, which results in intracellular signaling pathway activation [6][7]; although the existence of a Zn2+-sensing receptor was already suggested in 2001 by functional identification [5]. Zn2+ is found in all tissues in relatively high concentrations [9] and has been so far shown to activate GPR39 in bones, neurons, pancreatic cells, salivary gland cells, epithelial cells of the colon (colonocytes), epidermal cells of the skin (keratinocytes), skin fibroblasts, endothelial cells, cardiac valve interstitial cells, aortic vascular smooth muscle cells and prostate cancer cells [14][24][26][36][44][45][46][47][48][49][50]. Extracellular Zn2+, able to activate GPR39, can be released from the pancreatic β-cells together with insulin, nerve synapses together with glutamate, salivary gland vesicles, Paneth cells of the intestinal crypts or in connection with cell injury and death [14][15][16][51][52].

Importantly, endogenous physiological Zn2+ concentrations following release from vesicles or injury are able to activate GPR39 [14][15][21][47][53]. Physiological Zn2+ concentrations are in the nano-micromolar range, varying between tissues [9]. For example, in colonocytes the EC50 for GPR39 is 80 µM [26] whereas in keratinocytes it is in the nanomolar range [14], corresponding to the higher available Zn2+ concentrations in the colon compared to the skin [9]. Zn2+ binding to GPR39 and its consequent activation works concentration-dependently, resulting in the activation of all GPR39 mediated pathways, and signaling through Gαq, Gαs, Gα11/12 and β-arrestin recruitment [6][8][23][24]. The Zn2+ binding sites in GPR39 have been identified as histidine residues His17, His19 and aspartate residue Asp313 [54], and are conserved in the receptor of all vertebrates, excluding fish [55]. These residues have been shown to be pH sensitive; hence, physiological changes in extracellular pH directly affect and regulate GPR39 signaling [56]. pH levels both below and above the physiological 7.4 reduce GPR39 signaling drastically, eliminating the intracellular Ca2+ response and phosphorylation of PI3K completely at pH 6.4 [57], suggesting that GPR39 is strongly optimized for neutral pH levels. Fish GPR39 does not seem likely to be able to bind Zn2+; since GPR39 is present in fish, this could be an indication of another endogenous ligand existing for GPR39 in fish and possibly in other vertebrates [58]. The Zn2+-dependent activation of GPR39 has been characterized in many physiological and pathological conditions, reviewed in detail in Section 4. Ionic zinc is so far the only identified endogenous ligand for GPR39. However, it cannot be excluded that another endogenous ligand exists, since Zn2+ also has various other interaction partners [9][10], and novel synthetic ligands have been shown to be able to increase GPR39 signaling further than achieved solely by Zn2+, as will be discussed below. It is thus also possible that zinc is simply an enhancer and coactivator of another endogenous ligand, yet to be identified.

3.2. Synthetic Ligands of GPR39

Only a small number of synthetic ligands for GPR39 have been characterized. The best characterized and most widely published agonist to date is TC-G 1008 (originally known as GPR39-C3), but since its discovery, other potent agonists have been characterized. Since the first GPR39 agonist was discovered in 2013 [59] and shortly after in 2014 TC-G 1008, which quickly became commercially available [60], the number of studies focusing on GPR39 agonists has been steadily increasing in recent years. This has permitted the characterization of the physiological functions of GPR39 more specifically, compared to the GPR39-deficient or overexpressing mice, where global systemic compensatory mechanisms may play a role.

The first GPR39 agonist was a piperazine derivative, identified by a screening of GPCR-focused libraries against GPR39 [59]. The agonist was able to activate GPR39 and to induce the intracellular Ca2+ response, but turned out to be only moderately potent and not suitable for in vivo studies [59]. Soon after, in 2014, another research group identified 2-pyridylpyrimidines as potential GPR39 agonists via a reporter gene assay designed for identifying inhibitors of Hedgehog signaling, and then optimized them to improve efficiency and pharmacokinetics, which yielded TC-G 1008 [60]. It is a highly potent and selective GPR39 agonist with EC50 values of <1 nM, and orally bioavailable. When TC-G 1008 treatment was combined with Zn2+, more InsP was generated than with either substance alone, indicating that TC-G 1008 does not compete for binding with Zn2+, but the presence of Zn2+ further potentiates GPR39 activation by TC-G 1008. Originally, TC-G 1008 was also found to robustly induce glucagon-like peptide-1 (GLP-1) levels when orally administered to mice [60]. Later, it has been shown to activate all GPR39 inducible pathways [35]. Since its discovery, TC-G 1008 has proven to be a potent agonist and a very valuable tool in characterizing the physiological functions and therapeutic potential of GPR39 activation, published by a number of studies to date [30][31][32][35][61][62][63][64][65][66][67][68][69][70][71][72]. However, most studies have not verified their findings in GPR39−/− settings, which would be critical in order to confirm that the observed effects are indeed GPR39-dependent.

Additionally, in 2014, a series of cyclohexyl-methyl aminopyrimidine chemotype compounds (CMAPs) activating GPR39 was identified co-incidentally, while similarly screening for compounds that could inhibit Hedgehog signaling [73]. The identified compounds, which inhibited Hedgehog signaling, were also found to increase InsP production, indicating GPCR involvement. GPCR mRNA expression levels were correlated with the compound activity in different cell lines, which indicated the target of the compound to be GPR39, later verified with GPR39-deficient cells. The EC50 of the most potent compound CMAP 7 was 20 nM, thus the compound was not as potent as TC-G 1008. Importantly, this study showed that GPR39 activation interferes with Hedgehog signaling, which plays important roles in tumorigenesis and determines cell fate during development [73]. Shortly after, in 2015, three novel GPR39 agonists were described, AZ7914, AZ4237 and AZ1395 [74]. They were identified by a high throughput screen of the AstraZeneca compound library and were verified by a limited medicinal chemistry program. These compounds were also found to be more potent in the presence of Zn2+ and to interact directly with Zn2+. In a physiological characterization, these agonists were not able to improve glucose tolerance in lean or obese mice or in Zucker fatty rats. All three compounds had higher EC50 values than TC-G 1008, thus being less potent [74].

In 2016, two previously existing kinase inhibitors, the Janus kinase (JAK) inhibitor LY2784544 and the PI3Kβ inhibitor GSK2636771, were identified as novel GPR39 agonists by unbiased small-molecule-based screening of multiple compound libraries using a modified β-arrestin recruitment assay [65]. Their signaling patterns were compared to those of TC-G 1008, and GPR39 activation by all three compounds was shown to be allosterically modulated by physiological concentrations of Zn2+. As with TC-G 1008, the presence of Zn2+ increased the potency of LY2784544 and GSK2636771 to activate GPR39 and downstream signaling. Although LY2784544 and GSK2636771 were suggested to be more potent in activating GPR39 than inhibiting JAK2 and PI3Kβ, respectively, to date, these compounds have not been utilized in other GPR39 studies, likely due to not being exclusively selective for GPR39 [65]. However, one study used LY2784544 as a control for TC-G 1008 and found that both compounds similarly suppressed lipopolysaccharide (LPS) –induced interleukin 6 (IL6) production in macrophages [62]. Furthermore, as both compounds are being tested in clinical trials, their potential to activate GPR39 would be of great interest to study, as GPR39 activation might induce adverse effects or be partly responsible for the positive outcomes. Currently, according to www.clinicaltrials.gov, LY2784544 is being tested in myeloproliferative disorders and GSK2636771 in various cancers, most focusing on cancers with genetic changes of phosphatase and tensin homolog (PTEN).

Another novel set of GPR39 agonists were discovered in 2017 with the help of a homology model-based approach [75]. This model took advantage of a suggested binding site for synthetic ligands in GPR39 and commercially available libraries of synthetic compounds. Interestingly, some of the most potent identified compounds turned out to be inactive alone, but highly potent and selective in the presence of Zn2+ as an allosteric enhancer. Mutational mapping indicated that the synthetic agonists are able to bind to the main ligand binding pocket of GPR39, whereas Zn2+ seems to bind differently when acting as the sole agonist as compared to acting as an allosteric modulator. The selected agonist, TM-N1324 (compound 8 in [75]), had an EC50 of 280 nM and 9 nM in the absence and presence of Zn2+, respectively, thus being potent even in the absence of Zn2+. TM-N1324 could be orally administered and resulted in micromolar plasma concentrations, adequate for maximal activation of GPR39. With the help of this agonist, GPR39 was identified as an important regulator of gastric somatostatin secretion, increasing somatostatin secretion and correspondingly decreasing ghrelin secretion in primary gastric mucosal cells; an effect which was eliminated in GPR39−/− cells [75][76].

The first biased ligand, i.e., a ligand favoring selected signaling pathways over others, for GPR39 was discovered in 2017 [35]. GSB-118 was found through high-throughput screening of a compound library and by utilizing cAMP assays in the presence of Zn2+. It showed functional selectivity by activating the Gαs pathway, resulting in cAMP responses and β-arrestin recruitment, but did not activate the Gαq or Gα12/13 pathways, result in InsP accumulation or Ca2+ response, or desensitize GPR39. GSB-118 did not show any independent agonist activity but acted as a positive allosteric modulator for Zn2+, potentiating its responses [35]. The lack of desensitization observed here could attenuate drug tolerance and therefore, enhance responses to treatment. Development of more biased agonists targeting certain pathways more specifically rather than activating all GPR39-dependent signaling would allow for more targeted therapies and might be a key for future applications of GPR39 agonism for therapeutic purposes. More knowledge about the physiological functions of GPR39 and their molecular mechanisms in each disease is needed, before the development of signaling pathway-targeted therapies is meaningful. However, all identified synthetic ligands have not been fully characterized regarding signal transduction and might include some biased agonists. Despite being highly potent, the majority of these novel agonists presented here are more or less Zn2+-dependent, and thus it remains to be seen if they are sufficiently functional in tissues with lower physiological Zn2+ concentrations, and importantly, if they have therapeutic potential in conditions linked to Zn2+ deficiency. It is also still an open question whether at least some of the synthetic ligands simply function as allosteric activators of Zn2+ and not vice versa, as was suggested for GSB-118 [35]. Additionally, the GPR39-specificity of most ligands in physiological conditions will still need to be determined in GPR39−/− cell and tissue models.

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