Discovery and Characterization of Novel GPR39 Agonists Allosterically Modulated by Zinc

Sato, Seiji; Huang, Xi Ping; Kroeze, Wesley K.; Roth, Bryan L.

doi:10.1124/mol.116.106112

Cited by 49 publications

(78 citation statements)

References 89 publications

(72 reference statements)

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“…Activation of Gpr39 induces the release of Ca 2+ via the IP 3 pathway. The receptor may play a role in depression, and as a specific and direct sensor of Zn 2+ , in many physiological functions where the cation is involved such as synaptic transmission (Popovics and Stewart, 2011 ; Sato et al, 2016 ). Kisspeptin, encoded by the Kiss1 gene, is considered to have an emerging role in the neuroendocrine regulation of reproduction and puberty (de Roux et al, 2003 ; Seminara, 2006 ; Kauffman et al, 2007 ; Colledge, 2009 ).…”

Section: Discussionmentioning

confidence: 99%

Transcriptional Alterations in the Trigeminal Ganglia, Nucleus and Peripheral Blood Mononuclear Cells in a Rat Orofacial Pain Model

Aczél

Kun

Szöke

et al. 2018

Front. Mol. Neurosci.

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Orofacial pain and headache disorders are among the most debilitating pain conditions. While the pathophysiological basis of these disorders may be diverse, it is generally accepted that a common mechanism behind the arising pain is the sensitization of extra- and intracranial trigeminal primary afferents. In the present study we investigated gene expression changes in the trigeminal ganglia (TRG), trigeminal nucleus caudalis (TNC) and peripheral blood mononuclear cells (PBMC) evoked by Complete Freund's Adjuvant (CFA)-induced orofacial inflammation in rats, as a model of trigeminal sensitization. Microarray analysis revealed 512 differentially expressed genes between the ipsi- and contralateral TRG samples 7 days after CFA injection. Time-dependent expression changes of G-protein coupled receptor 39 (Gpr39), kisspeptin-1 receptor (Kiss1r), kisspeptin (Kiss1), as well as synaptic plasticity-associated Lkaaear1 (Lkr) and Neurod2 mRNA were described on the basis of qPCR results. The greatest alterations were observed on day 3 ipsilaterally, when orofacial mechanical allodynia reached its maximum. This corresponded well with patterns of neuronal (Fosb), microglia (Iba1), and astrocyte (Gfap) activation markers in both TRG and TNC, and interestingly also in PBMCs. This is the first description of up- and downregulated genes both in primary and secondary sensory neurones of the trigeminovascular system that might play important roles in neuroinflammatory activation mechanisms. We are the first to show transcriptomic alterations in the PBMCs that are similar to the neuronal changes. These results open new perspectives and initiate further investigations in the research of trigeminal pain disorders.

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Section: Discussionmentioning

confidence: 99%

Transcriptional Alterations in the Trigeminal Ganglia, Nucleus and Peripheral Blood Mononuclear Cells in a Rat Orofacial Pain Model

Aczél

Kun

Szöke

et al. 2018

Front. Mol. Neurosci.

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“…A recent report demonstrated an unexpected role of zinc at GPR39, a member of the ghrelin peptide receptor family. In addition to activation of GPR39, which is described as a Zn 2+ -sensing receptor, zinc also allosterically enhanced intracellular signaling induced by two novel small-molecule agonists of GPR39: LY2784544 and GSK2636771 [ 19 ].…”

Section: Introductionmentioning

confidence: 99%

Allosteric Inhibition of Serotonin 5-HT7 Receptors by Zinc Ions

et al. 2017

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The allosteric regulation of G protein-coupled receptors (GPCRs) is a well-known phenomenon, but there are only a few examples of allosteric modulation within the metabotropic serotonergic receptor family. Recently, we described zinc non-competitive interactions toward agonist binding at serotonin 5-HT1A receptors, in which biphasic effects, involving potentiation at sub-micromolar concentrations (10 μM) and inhibition at sub-millimolar concentrations (500 μM) of Zn2+ in radioligand binding assays, were consistent with both the agonist and antagonist-like effects of zinc ions observed in in vivo studies. Here, we showed new data demonstrating zinc allosteric inhibition of both agonist and antagonist binding at human recombinant 5-HT7 receptors stably expressed in HEK293 cells as observed by radioligand binding studies as well as zinc neutral antagonism displayed by the concentration of 10 μM in the functional LANCE assay. The allosteric nature of the effect of Zn on 5-HT7 receptors was confirmed (1) in saturation studies in which zinc inhibited the binding of potent orthosteric 5-HT7 receptor radioligands, the agonist [3H]5-CT, and the two antagonists [3H]SB-269970 and [3H]mesulergine, showing ceiling effect and differences in the magnitude of negative cooperativity (α = 0.15, 0.06, and 0.25, respectively); (2) in competition experiments in which 500 μM of zinc inhibited all radioligand displacements by non-labeled orthosteric ligands (5-CT, SB-269970, and clozapine), and the most significant reduction in affinity was observed for the 5-CT agonist (4.9–16.7-fold) compared with both antagonists (1.4–3.9-fold); and (3) in kinetic experiments in which 500 μM zinc increased the dissociation rate constants for [3H]5-CT and [3H]mesulergine but not for [3H]SB-269970. Additionally, in the functional LANCE test using the constitutively active HEK293 cell line expressing the 5-HT7 receptor, 10 μM zinc had features of neutral antagonism and increased the EC50 value of the 5-CT agonist by a factor of 3.2. Overall, these results showed that zinc can act as a negative allosteric inhibitor of 5-HT7 receptors. Given that the inhibiting effects of low concentrations of zinc in the functional assay represent the most likely direction of zinc activity under physiological conditions, among numerous zinc-regulated proteins, the 5-HT7 receptor can be considered a serotonergic target for zinc modulation in the CNS.

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“…However, it is unclear if the pharmacokinetics of Zn 2+ with GPR39 support it as a physiological agonist of the receptor. It is more likely that zinc modulates receptor activity based on studies characterizing synthetic GPR39 agonists (17). Furthermore, Zn 2+ is known to be an allosteric modulator for multiple receptors and ion channels (31).…”

Section: Discussionmentioning

confidence: 99%

“…Zinc has been reported to be either a GPR39 agonist (14) or an allosteric modulator for synthetic ligands of the receptor (17). Therefore, we first tested the effect of Zn 2+ alone in mVSMCs and found that it increased intracellular calcium at concentrations ≥20 M ( Fig 3E) and had no effect at concentrations between 1-10 M (Fig 3F).…”

Section: Zinc Sensitizes Gpr39 To 1415-eet and 15-hetementioning

confidence: 95%

Bidirectional Control of Coronary Vascular Resistance by Eicosanoids via a Novel GPCR

Alkayed

Cao

Qian

et al. 2018

Preprint

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Arachidonic acid metabolites epoxyeicosatrienoates (EETs) and hydroxyeicosatetraenoates (HETEs) are important regulators of myocardial blood flow and coronary vascular resistance (CVR), but their mechanisms of action are not fully understood. We identified G protein-coupled receptor 39 (GPR39) as a microvascular smooth muscle cell (mVSMC) receptor antagonistically regulated by two endogenous eicosanoids: 15-HETE, which stimulates GPR39 to increase mVSMC intracellular calcium and augment microvascular CVR, and 14,15-EET, which inhibits these actions. Furthermore, zinc ion acts as an allosteric modulator of GPR39 to potentiate the efficacy of the two ligands. Our findings will have a major impact on understanding the roles of eicosanoids in cardiovascular physiology and disease, and provide an opportunity for the development of novel GPR39-targeting therapies for cardiovascular disease.One Sentence Summary: GPR39 is a microvascular smooth muscle cell receptor regulated by two vasoactive eicosanoids with opposing actions. Main Text:Myocardial oxygen demand determines coronary blood flow, which is exquisitely regulated through changing vascular resistance in coronary arterioles ranging in size from 100µm to 300µm (1). Whereas the determinants of myocardial oxygen demand are well known, the molecules responsible for the second-to-second regulation of microvascular tone and the receptors through which they act have not been identified. Two classes of signaling P450 eicosanoids, epoxyeicosatrienoates (EETs) and hydroxyeicosatetraenoates (HETEs), are potent regulators of microvascular tone and play critical roles in cardiovascular physiology and disease (2, 3). EETs are predominantly microvascular dilators and have been shown to function as endothelium-derived

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Discovery and Characterization of Novel GPR39 Agonists Allosterically Modulated by Zinc

Cited by 49 publications

References 89 publications

Transcriptional Alterations in the Trigeminal Ganglia, Nucleus and Peripheral Blood Mononuclear Cells in a Rat Orofacial Pain Model

Transcriptional Alterations in the Trigeminal Ganglia, Nucleus and Peripheral Blood Mononuclear Cells in a Rat Orofacial Pain Model

Allosteric Inhibition of Serotonin 5-HT7 Receptors by Zinc Ions

Bidirectional Control of Coronary Vascular Resistance by Eicosanoids via a Novel GPCR

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