The orphan receptor GPR139 signals via Gq/11 to oppose opioid effects

Abstract

The interplay between G protein–coupled receptors (GPCRs) is critical for controlling neuronal activity that shapes neuromodulatory outcomes. Recent evidence indicates that the orphan receptor GPR139 influences opioid modulation of key brain circuits by opposing the actions of the µ-opioid receptor (MOR). However, the function of GPR139 and its signaling mechanisms are poorly understood. In this study, we report that GPR139 activates multiple heterotrimeric G proteins, including members of the Gq/11 and Gi/o families. Using a panel of reporter assays in reconstituted HEK293T/17 cells, we found that GPR139 functions via the Gq/11 pathway and thereby distinctly regulates cellular effector systems, including stimulation of cAMP production and inhibition of G protein inward rectifying potassium (GIRK) channels. Electrophysiological recordings from medial habenular neurons revealed that GPR139 signaling via Gq/11 is necessary and sufficient for counteracting MOR-mediated inhibition of neuronal firing. These results uncover a mechanistic interplay between GPCRs involved in controlling opioidergic neuromodulation in the brain. The interplay between G protein–coupled receptors (GPCRs) is critical for controlling neuronal activity that shapes neuromodulatory outcomes. Recent evidence indicates that the orphan receptor GPR139 influences opioid modulation of key brain circuits by opposing the actions of the µ-opioid receptor (MOR). However, the function of GPR139 and its signaling mechanisms are poorly understood. In this study, we report that GPR139 activates multiple heterotrimeric G proteins, including members of the Gq/11 and Gi/o families. Using a panel of reporter assays in reconstituted HEK293T/17 cells, we found that GPR139 functions via the Gq/11 pathway and thereby distinctly regulates cellular effector systems, including stimulation of cAMP production and inhibition of G protein inward rectifying potassium (GIRK) channels. Electrophysiological recordings from medial habenular neurons revealed that GPR139 signaling via Gq/11 is necessary and sufficient for counteracting MOR-mediated inhibition of neuronal firing. These results uncover a mechanistic interplay between GPCRs involved in controlling opioidergic neuromodulation in the brain. The mammalian brain features a staggering number of neuromodulatory systems that often converge on the same neurons and must be integrated and balanced through a system of opposing signaling and feedback mechanisms (1Huang Y. Thathiah A. Regulation of neuronal communication by G protein-coupled receptors.FEBS Lett. 2015; 589 (25980603): 1607-161910.1016/j.febslet.2015.05.007Crossref PubMed Scopus (52) Google Scholar). Most neuromodulators act on G protein–coupled receptors (GPCRs), an extensive protein family that triggers responses by engaging second messenger systems and ion channels. GPCR signals are relayed through an array of heterotrimeric G proteins comprised of 16 Gα subunits (2Milligan G. Kostenis E. Heterotrimeric G-proteins: a short history.Br. J. Pharmacol. 2006; 147 (16402120): S46-S5510.1038/sj.bjp.0706405Crossref PubMed Scopus (259) Google Scholar). The G protein(s) activated by a GPCR dictates the nature of the signal by engaging specific downstream targets. Ultimately, neuronal responses are built from cross-talk between GPCRs engaged by neuromodulatory inputs (1Huang Y. Thathiah A. Regulation of neuronal communication by G protein-coupled receptors.FEBS Lett. 2015; 589 (25980603): 1607-161910.1016/j.febslet.2015.05.007Crossref PubMed Scopus (52) Google Scholar, 3Greengard P. The neurobiology of slow synaptic transmission.Science. 2001; 294 (11691979): 1024-103010.1126/science.294.5544.1024Crossref PubMed Scopus (680) Google Scholar). Understanding the logic and mechanisms of this GPCR signaling coordination is critical yet poorly explored. Recently, we uncovered a novel regulatory GPCR system that revolves around GPR139 antagonizing the μ-opioid receptor (MOR) (4Wang D. Stoveken H.M. Zucca S. Dao M. Orlandi C. Song C. Masuho I. Johnston C. Opperman K.J. Giles A.C. Gill M.S. Lundquist E.A. Grill B. Martemyanov K.A. Genetic behavioral screen identifies an orphan anti-opioid system.Science. 2019; 365 (31416932): 1267-127310.1126/science.aau2078Crossref PubMed Scopus (15) Google Scholar). MOR couples to the Gi/o class of heterotrimeric G proteins to inhibit production of second messenger cAMP and to activate G protein inwardly rectifying potassium (GIRK) channels (5Al-Hasani R. Bruchas M.R. Molecular mechanisms of opioid receptor-dependent signaling and behavior.Anesthesiology. 2011; 115 (22020140): 1363-138110.1097/ALN.0b013e318238bba6Crossref PubMed Scopus (490) Google Scholar). It has been heavily targeted therapeutically for its desirable analgesic effects (6Chen Y. Mestek A. Liu J. Hurley J.A. Yu L. Molecular cloning and functional expression of a μ-opioid receptor from rat brain.Mol. Pharmacol. 1993; 44 (8393525): 8-12PubMed Google Scholar, 7Matthes H.W. Maldonado R. Simonin F. Valverde O. Slowe S. Kitchen I. Befort K. Dierich A. Le Meur M. Dollé P. Tzavara E. Hanoune J. Roques B.P. Kieffer B.L. 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Our initial examination of the intersection between MOR and GPR139 revealed that multiple aspects of MOR signaling were impinged by GPR139, which could be aided by a physical interaction between the receptors (4Wang D. Stoveken H.M. Zucca S. Dao M. Orlandi C. Song C. Masuho I. Johnston C. Opperman K.J. Giles A.C. Gill M.S. Lundquist E.A. Grill B. Martemyanov K.A. Genetic behavioral screen identifies an orphan anti-opioid system.Science. 2019; 365 (31416932): 1267-127310.1126/science.aau2078Crossref PubMed Scopus (15) Google Scholar). For instance, GPR139 enhanced β-arrestin recruitment to activated MOR and moderated its coupling to GIRK channels (4Wang D. Stoveken H.M. Zucca S. Dao M. Orlandi C. Song C. Masuho I. Johnston C. Opperman K.J. Giles A.C. Gill M.S. Lundquist E.A. Grill B. Martemyanov K.A. Genetic behavioral screen identifies an orphan anti-opioid system.Science. 2019; 365 (31416932): 1267-127310.1126/science.aau2078Crossref PubMed Scopus (15) Google Scholar). However, the exact mechanism(s) of how GPR139 exerts an inhibitory influence on MOR and its relevance to the regulation of neuronal responses remains unknown. The biology and signaling mechanisms of GPR139 are also poorly understood. It is an orphan GPCR expressed in select circuits in the brain, most notably in the areas implicated in motivation and reward (13Liu C. Bonaventure P. Lee G. Nepomuceno D. Kuei C. Wu J. Li Q. Joseph V. Sutton S.W. Eckert W. Yao X. Yieh L. Dvorak C. Carruthers N. Coate H. et al.GPR139, an orphan receptor highly enriched in the habenula and septum, is activated by the essential amino acids l-tryptophan and l-phenylalanine.Mol. Pharmacol. 2015; 88 (26349500): 911-92510.1124/mol.115.100412Crossref PubMed Scopus (29) Google Scholar, 14Matsuo A. Matsumoto S. Nagano M. Masumoto K.H. Takasaki J. Matsumoto M. Kobori M. Katoh M. Shigeyoshi Y. Molecular cloning and characterization of a novel Gq-coupled orphan receptor GPRg1 exclusively expressed in the central nervous system.Biochem. Biophys. Res. Commun. 2005; 331 (15845401): 363-36910.1016/j.bbrc.2005.03.174Crossref PubMed Scopus (42) Google Scholar, 15Süsens U. Hermans-Borgmeyer I. Urny J. Schaller H.C. Characterisation and differential expression of two very closely related G-protein-coupled receptors, GPR139 and GPR142, in mouse tissue and during mouse development.Neuropharmacology. 2006; 50 (16378626): 512-52010.1016/j.neuropharm.2005.11.003Crossref PubMed Scopus (38) Google Scholar). Whereas the endogenous ligand for GPR139 is a lingering question, it has been shown to be activated by the amino acids l-Phe and l-Trp and the neuropeptide α-MSH (13Liu C. Bonaventure P. Lee G. Nepomuceno D. Kuei C. Wu J. Li Q. Joseph V. Sutton S.W. Eckert W. Yao X. Yieh L. Dvorak C. Carruthers N. Coate H. et al.GPR139, an orphan receptor highly enriched in the habenula and septum, is activated by the essential amino acids l-tryptophan and l-phenylalanine.Mol. Pharmacol. 2015; 88 (26349500): 911-92510.1124/mol.115.100412Crossref PubMed Scopus (29) Google Scholar, 16Isberg V. Andersen K.B. Bisig C. Dietz G.P. Bräuner-Osborne H. Gloriam D.E. Computer-aided discovery of aromatic l-α-amino acids as agonists of the orphan G protein-coupled receptor GPR139.J. Chem. Inf. Model. 2014; 54 (24826842): 1553-155710.1021/ci500197aCrossref PubMed Scopus (29) Google Scholar, 17Nøhr A.C. Shehata M.A. Hauser A.S. Isberg V. Mokrosinski J. Andersen K.B. Farooqi I.S. Pedersen D.S. Gloriam D.E. Bräuner-Osborne H. The orphan G protein-coupled receptor GPR139 is activated by the peptides: adrenocorticotropic hormone (ACTH), α-, and β-melanocyte stimulating hormone (α-MSH, and β-MSH), and the conserved core motif HFRW.Neurochem. Int. 2017; 102 (27916541): 105-11310.1016/j.neuint.2016.11.012Crossref PubMed Scopus (20) Google Scholar). Additionally, several synthetic ligands can activate GPR139 with high efficiency (18Dvorak C.A. Coate H. Nepomuceno D. Wennerholm M. Kuei C. Lord B. Woody D. Bonaventure P. Liu C. Lovenberg T. Carruthers N.I. Identification and SAR of glycine benzamides as potent agonists for the GPR139 receptor.ACS Med. Chem. Lett. 2015; 6 (26396690): 1015-101810.1021/acsmedchemlett.5b00247Crossref PubMed Scopus (20) Google Scholar, 19Nøhr A.C. Shehata M.A. Palmer D. Pokhrel R. Vallianou M. Foster S.R. Gentry P.R. Gloriam D.E. Bräuner-Osborne H. Identification of a novel scaffold for a small molecule GPR139 receptor agonist.Sci. Rep. 2019; 9 (30846711): 380210.1038/s41598-019-40085-9Crossref PubMed Scopus (3) Google Scholar, 20Shi F. Shen J.K. Chen D. Fog K. Thirstrup K. Hentzer M. Karlsson J.J. Menon V. Jones K.A. Smith K.E. Smith G. Discovery and SAR of a series of agonists orphan G protein-coupled receptor Med. Chem. Lett. 2011; PubMed Scopus Google Scholar). also shown that GPR139 a of second messenger in A. Matsumoto S. Nagano M. Masumoto K.H. Takasaki J. Matsumoto M. Kobori M. Katoh M. Shigeyoshi Y. Molecular cloning and characterization of a novel Gq-coupled orphan receptor GPRg1 exclusively expressed in the central nervous system.Biochem. Biophys. Res. Commun. 2005; 331 (15845401): 363-36910.1016/j.bbrc.2005.03.174Crossref PubMed Scopus (42) Google Scholar, 15Süsens U. Hermans-Borgmeyer I. Urny J. Schaller H.C. Characterisation and differential expression of two very closely related G-protein-coupled receptors, GPR139 and GPR142, in mouse tissue and during mouse development.Neuropharmacology. 2006; 50 (16378626): 512-52010.1016/j.neuropharm.2005.11.003Crossref PubMed Scopus (38) Google Scholar, T. J. Liu Q. Identification of agonists and for orphan G-protein-coupled receptor GPR139.J. PubMed Scopus Google Scholar). However, its coupling to G proteins and in downstream signals has been which of the we the results of a of G of GPR139 and its in signaling to downstream also how GPR139 regulates MOR effects in a neuronal that the key effects of GPR139 are by Gq/11 which the of MOR signals several on we that GPR139 cellular responses to opioid the signaling of GPR139, we its G a GPCR that the of receptors and Gα proteins to coupling I. O. Jones K. Martemyanov K.A. of functional G proteins the actions of G protein-coupled 2015; PubMed Scopus Google Scholar). In this with the In the of a Gα GPCR activation triggers of the G protein the signal Using this we GPR139 activity on Gα proteins and the and initial activation for G protein G and GPR139 could activate multiple G proteins with and the Gi/o were for subtypes and the Gq/11 and activation with members of GPR139 coupling to and and were activated by GPR139 and of and the activation of G proteins revealed a of GPR139 coupling results that GPR139 is a receptor of G proteins of the Gi/o and Gq/11 GPR139 can activate multiple G protein which can to cellular we the engaged by a panel of to the effect of GPR139 activation on ion and cAMP were with the J. D. S. D. D. stimulation with Commun. PubMed Scopus Google we that GPR139 activation a and in signal of from and with A. Matsumoto S. Nagano M. Masumoto K.H. Takasaki J. Matsumoto M. Kobori M. Katoh M. Shigeyoshi Y. Molecular cloning and characterization of a novel Gq-coupled orphan receptor GPRg1 exclusively expressed in the central nervous system.Biochem. Biophys. Res. Commun. 2005; 331 (15845401): 363-36910.1016/j.bbrc.2005.03.174Crossref PubMed Scopus (42) Google Scholar, 15Süsens U. Hermans-Borgmeyer I. Urny J. Schaller H.C. Characterisation and differential expression of two very closely related G-protein-coupled receptors, GPR139 and GPR142, in mouse tissue and during mouse development.Neuropharmacology. 2006; 50 (16378626): 512-52010.1016/j.neuropharm.2005.11.003Crossref PubMed Scopus (38) Google Scholar). 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Dvorak C. Carruthers N. Coate H. et al.GPR139, an orphan receptor highly enriched in the habenula and septum, is activated by the essential amino acids l-tryptophan and l-phenylalanine.Mol. Pharmacol. 2015; 88 (26349500): 911-92510.1124/mol.115.100412Crossref PubMed Scopus (29) Google and the effects of and (4Wang D. Stoveken H.M. Zucca S. Dao M. Orlandi C. Song C. Masuho I. Johnston C. Opperman K.J. Giles A.C. Gill M.S. Lundquist E.A. Grill B. Martemyanov K.A. Genetic behavioral screen identifies an orphan anti-opioid system.Science. 2019; 365 (31416932): 1267-127310.1126/science.aau2078Crossref PubMed Scopus (15) Google Scholar, J. M. A. D. G. O. and activation of the orphan G protein-coupled receptor GPR139 and in 2018; PubMed Scopus Google Scholar). found that GPR139 is with MOR and its the of a for GPR139 in reward (4Wang D. Stoveken H.M. Zucca S. Dao M. Orlandi C. Song C. Masuho I. Johnston C. Opperman K.J. Giles A.C. Gill M.S. Lundquist E.A. Grill B. Martemyanov K.A. Genetic behavioral screen identifies an orphan anti-opioid system.Science. 2019; 365 (31416932): 1267-127310.1126/science.aau2078Crossref PubMed Scopus (15) Google Scholar). In this we critical GPR139 signaling that GPR139 the Gq/11 pathway to activate and inhibit the GIRK key effector that are in an by thereby a mechanistic for the signaling cross-talk that this signaling is essential for to inhibit opioid effects in The Gq/11 in this the inhibitory effects of GPR139 on MOR by β-arrestin recruitment and (4Wang D. Stoveken H.M. Zucca S. Dao M. Orlandi C. Song C. Masuho I. Johnston C. Opperman K.J. Giles A.C. Gill M.S. Lundquist E.A. Grill B. Martemyanov K.A. Genetic behavioral screen identifies an orphan anti-opioid system.Science. 2019; 365 (31416932): 1267-127310.1126/science.aau2078Crossref PubMed Scopus (15) Google Scholar). Our that GPR139 Gq/11 to MOR signaling by Gi/o a of the signaling cross-talk that the of G proteins to The interplay between Gq/11 and Gi/o has been for ion channels and and Ther. 2017; PubMed Scopus Google Scholar, A. Y. channels as of Biophys. 2014; PubMed Scopus (20) Google Scholar). In opposing signaling between and has been in C. J. Heterotrimeric G proteins in C. 2006; Google Scholar, Chen G. M.R. between and in the protein is necessary for signaling and regulates PubMed Scopus Google Scholar, and the pathway in C. Full Text Full Text PDF PubMed Scopus Google Scholar). the receptors act with receptors to signaling P. of receptors and receptors, which act via G proteins, and in U. S. A. PubMed Scopus Google Scholar, N. T. H.M. R. activation from by Res. PubMed Scopus Google Scholar, A. K.A. M. S. Y. H. of and proteins exerts effect on human through activation of and Med. PubMed Scopus Google Scholar). the cellular Gq/11 and Gi/o an inhibitory the of cross-talk is and it that regulation of effector systems in neuronal that Gq/11 signaling by GPR139 also with the Gi/o signals by GPCRs with a and the of GPCR by GPR139 remains to be this it is that a a functional interaction between GPR139 and the receptor L. Lee G. Kuei C. Yao X. A. Bonaventure P. Lovenberg Liu C. GPR139 and receptor in the same of the brain and Neurosci. 2019; PubMed Google Scholar). The interplay of GPR139 with GPCRs from we for MOR and be by and cellular Our of G protein coupling revealed that GPR139 can activate multiple G Whereas this the of the Gq/11 in GPR139 effects on opioid the relevance and of signaling to be It that Gα GPR139 effects it to signaling are by the coupling of GPR139 to the Gi/o coupling in the of Gi/o to from that yet Gi/o is to be two mechanisms that could this activation of Gi/o to the Gq/11 signals GPR139 with a Gi/o signaling be in neuronal the Gq/11 is of cellular signaling by GPR139, on the G protein in a In the of G protein in this of GPR139 signaling in key in GPR139 is related to its activation GPR139 activity in the of in which high GPR139 could this inhibitory influence to the of MOR to endogenous opioid In GPR139 could also be by The amino acids l-Phe and l-Trp been to activate GPR139 with an in the V. Andersen K.B. Bisig C. Dietz G.P. Bräuner-Osborne H. Gloriam D.E. Computer-aided discovery of aromatic l-α-amino acids as agonists of the orphan G protein-coupled receptor GPR139.J. Chem. Inf. Model. 2014; 54 (24826842): 1553-155710.1021/ci500197aCrossref PubMed Scopus (29) Google Scholar). These amino acids are in the a and GPR139 GPR139 could also be activated by several most are A.C. Shehata M.A. Hauser A.S. Isberg V. Mokrosinski J. Andersen K.B. Farooqi I.S. Pedersen D.S. Gloriam D.E. Bräuner-Osborne H. The orphan G protein-coupled receptor GPR139 is activated by the peptides: adrenocorticotropic hormone (ACTH), α-, and β-melanocyte stimulating hormone (α-MSH, and β-MSH), and the conserved core motif HFRW.Neurochem. Int. 2017; 102 (27916541): 105-11310.1016/j.neuint.2016.11.012Crossref PubMed Scopus (20) Google Scholar, D. Kuei C. Dvorak C. Lovenberg T. Liu C. Bonaventure P. of adrenocorticotropic hormone and stimulating hormone activation of GPR139 in Pharmacol. 2018; 9 PubMed Scopus Google Scholar). are involved in GPR139 modulation of opioid signaling in endogenous circuits remains to be Our a for the of that GPR139 agonists be to the behavioral to to most potency and and are of for in T. J. Liu Q. Identification of agonists and for orphan G-protein-coupled receptor GPR139.J. PubMed Scopus Google Scholar, J. Liu Q. Hentzer M. Smith G.P. of for the orphan receptor Pharmacol. 2015; PubMed Scopus Google Scholar). of GPR139 in the brain, its anti-opioid and the demonstration of its signaling mechanisms in this this orphan receptor an amino and balanced with and were from from cAMP and the cAMP were from as (18Dvorak C.A. Coate H. Nepomuceno D. Wennerholm M. Kuei C. Lord B. Woody D. Bonaventure P. Liu C. Lovenberg T. Carruthers N.I. Identification and SAR of glycine benzamides as potent agonists for the GPR139 receptor.ACS Med. Chem. Lett. 2015; 6 (26396690): 1015-101810.1021/acsmedchemlett.5b00247Crossref PubMed Scopus (20) Google Scholar). from The GPR139 for an signal by an and human GPR139 HEK293T/17 were in amino and were as I. Martemyanov K.A. G protein activation in with 2015; PubMed Scopus Google Scholar). HEK293T/17 were with and of of of the Gα Additionally, of of and of were and were balanced to 10 and assays were as I. O. Jones K. Martemyanov K.A. of functional G proteins the actions of G protein-coupled 2015; PubMed Scopus Google Scholar). HEK293T/17 were with of and of and and the as I. S. K. L. Martemyanov K.A. Molecular to mechanisms by GPCR Rep. 2018; Full Text Full Text PDF PubMed Scopus Google the were of of and of cAMP The were in a in for and The with of cAMP and as Y. Orlandi C. Martemyanov K.A. protein is a of receptors in U. S. A. 2018; 115 PubMed Scopus Google Scholar). GIRK function the Molecular potassium The were of of of of of rat of of and for the of were for and The were of a and with 10 were for an the of the of to of the were in the for signaling for 10 the were as and the in activation by a to the the initial of activation mice were by the and and were in with of of were with and Brain were and recordings from habenular neurons were as (4Wang D. Stoveken H.M. Zucca S. Dao M. Orlandi C. Song C. Masuho I. Johnston C. Opperman K.J. Giles A.C. Gill M.S. Lundquist E.A. Grill B. Martemyanov K.A. Genetic behavioral screen identifies an orphan anti-opioid system.Science. 2019; 365 (31416932): 1267-127310.1126/science.aau2078Crossref PubMed Scopus (15) Google Scholar). in were as the of the of the recordings in the of the with to the of the signals were high in the can be for mouse and K. for with G protein–coupled receptor µ-opioid receptor G protein inward rectifying potassium medial habenula signal

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