Publications HAL

2020

Journal articles

titre: Facilitating mGluR4 activity reverses the long-term deleterious consequences of chronic morphine exposure in male mice
auteur: Jérôme Aj Becker, Lucie P. Pellissier, Yannick Corde, Thibaut Laboute, Audrey Léauté, Jorge Gandía, Julie Le Merrer
article: Neuropsychopharmacology, 2020, pp.1-13. ⟨10.1038/s41386-020-00927-x⟩
resume: Understanding the neurobiological underpinnings of abstinence from drugs of abuse is critical to allow better recovery and ensure relapse prevention in addicted subjects. By comparing the long-term transcriptional consequences of morphine and cocaine exposure, we identified the metabotropic glutamate receptor subtype 4 (mGluR4) as a promising pharmacological target in morphine abstinence. We evaluated the behavioral and molecular effects of facilitating mGluR4 activity in abstinent mice. Transcriptional regulation of marker genes of medium spiny neurons (MSNs) allowed best discriminating between 4-week morphine and cocaine abstinence in the nucleus accumbens (NAc). Among these markers, Grm4, encoding mGluR4, displayed down-regulated expression in the caudate putamen and NAc of morphine, but not cocaine, abstinent mice. Chronic administration of the mGluR4 positive allosteric modulator (PAM) VU0155041 (2.5 and 5 mg/kg) rescued social behavior, normalized stereotypies and anxiety and blunted locomotor sensitization in morphine abstinent mice. This treatment improved social preference but increased stereotypies in cocaine abstinent mice. Finally, the beneficial behavioral effects of VU0155041 treatment in morphine abstinent mice were correlated with restored expression of key MSN and neural activity marker genes in the NAc. This study reports that chronic administration of the mGluR4 PAM VU0155041 relieves long-term deleterious consequences of morphine exposure. It illustrates the neurobiological differences between opiate and psychostimulant abstinence and points to pharmacological repression of excessive activity of D2-MSNs in the NAc as a promising therapeutic lever in drug addiction.
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titre: Membrane Estrogen Receptor (GPER) and Follicle-Stimulating Hormone Receptor (FSHR) Heteromeric Complexes Promote Human Ovarian Follicle Survival
auteur: Livio Casarini, Clara Lazzaretti, Elia Paradiso, Silvia Limoncella, Laura Riccetti, Samantha Sperduti, Beatrice Melli, Serena Marcozzi, Claudia Anzivino, Niamh S Sayers, Jakub Czapinski, Giulia Brigante, Francesco Potì, Antonio La Marca, Francesco de Pascali, Eric Reiter, Angela Falbo, Jessica Daolio, Maria Teresa Villani, Monica Lispi, Giovanna Orlando, Francesca Klinger, Francesca Fanelli, Adolfo Rivero-Müller, Aylin Hanyaloglu, Manuela Simoni
article: iScience, 2020, 23 (12), pp.1-58. ⟨10.1016/j.isci.2020.101812⟩
resume: Classically, follicle-stimulating hormone receptor (FSHR)-driven cAMP-mediated signaling boosts human ovarian follicle growth and oocyte maturation. However, contradicting in vitro data suggest a different view on physiological significance of FSHR-mediated cAMP signaling. We found that the G-protein-coupled estrogen receptor (GPER) heteromerizes with FSHR, reprogramming cAMP/death signals into proliferative stimuli fundamental for sustaining oocyte survival. In human granulosa cells, survival signals are missing at high FSHR:GPER ratio,which negatively impacts follicle maturation and strongly correlates with preferential Gas protein/cAMP-pathway coupling and FSH responsiveness of patients undergoing controlled ovarian stimulation. In contrast, FSHR/GPER heteromer striggered anti-apoptotic/proliferative FSH signaling delivered via the Gbgdimer, where as impairment of heteromer formation or GPER knockdown enhanced the FSH-dependent cell death and steroidogenesis. Therefore, our findings indicate how oocyte maturation depends on the capability of GPER to shape FSHR selective signals, indicating hormone receptor heteromers may be a marker of cell proliferation
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titre: Pharmacological Programming of Endosomal Signaling Activated by Small Molecule Ligands of the Follicle Stimulating Hormone Receptor
auteur: Silvia Sposini, Francesco de Pascali, Rachel Richardson, Niamh S Sayers, David Perrais, Henry N Yu, Stephen Palmer, Selva Nataraja, Eric Reiter, Aylin C Hanyaloglu
article: Frontiers in Pharmacology, 2020, 11, pp.1-14. ⟨10.3389/fphar.2020.593492⟩
resume: Follicle-stimulating hormone receptor (FSHR) is a G protein-coupled receptor (GPCR) with pivotal roles in reproduction. One key mechanism dictating the signal activity of GPCRs is membrane trafficking. After binding its hormone FSH, FSHR undergoes internalization to very early endosomes (VEEs) for its acute signaling and sorting to a rapid recycling pathway. The VEE is a heterogeneous compartment containing the Adaptor Protein Phosphotyrosine Interacting with Pleckstrin homology Domain and Leucine Zipper 1 (APPL1) with distinct functions in regulating endosomal Gαs/cAMP signaling and rapid recycling. Low molecular weight (LMW) allosteric FSHR ligands were developed for use in assisted reproductive technology yet could also provide novel pharmacological tools to study FSHR. Given the critical nature of receptor internalization and endosomal signaling for FSHR activity, we assessed whether these compounds exhibit differential abilities to alter receptor endosomal trafficking and signaling within the VEE. Two chemically distinct LMW agonists (benzamide, termed B3 and thiazolidinone, termed T1) were employed. T1 was able to induce a greater level of cAMP than FSH and B3. As cAMP signaling drives gonadotrophin hormone receptor recycling, rapid exocytic events were evaluated at single event resolution. Strikingly, T1 was able to induce a 3-fold increase in recycling events compared to FSH and two-fold more compared to B3. As T1-induced internalization was only marginally greater, the dramatic increase in recycling and cAMP signaling may be due to additional mechanisms. All compounds exhibited a similar requirement for receptor internalization to increase cAMP and proportion of FSHR endosomes with active Gαs, suggesting regulation of cAMP signaling induced by T1 may be altered. APPL1 plays a central role for GPCRs targeted to the VEE, and indeed, loss of APPL1 inhibited FSHinduced recycling and increased endosomal cAMP signaling. While T1-induced FSHR recycling was APPL1-dependent, its elevated cAMP signaling was only partially increased following APPL1 knockdown. Unexpectedly, B3 altered the dependence of FSHR to APPL1 in an opposing manner, whereby its endosomal signaling was negatively regulated by APPL1, while B3-induced FSHR recycling was APPL1-independent. Overall, FSHR allosteric compounds have the potential to reprogram FSHR activity via altering engagement with VEE machinery and also suggests that these two distinct functions of APPL1 can potentially be selected pharmacologically.
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titre: Cell communications among microorganisms, plants, and animals: origin, evolution, and interplays
auteur: Yves Combarnous, Thi Mong Diep Nguyen
article: International Journal of Molecular Sciences, 2020, 21 (21), pp.1-22. ⟨10.3390/ijms21218052⟩
resume: Cellular communications play pivotal roles in multi-cellular species, but they do so also in uni-cellular species. Moreover, cells communicate with each other not only within the same individual, but also with cells in other individuals belonging to the same or other species. These communications occur between two unicellular species, two multicellular species, or between unicellular and multicellular species. The molecular mechanisms involved exhibit diversity and specificity, but they share common basic features, which allow common pathways of communication between different species, often phylogenetically very distant. These interactions are possible by the high degree of conservation of the basic molecular mechanisms of interaction of many ligand-receptor pairs in evolutionary remote species. These inter-species cellular communications played crucial roles during Evolution and must have been positively selected, particularly when collectively beneficial in hostile environments. It is likely that communications between cells did not arise after their emergence, but were part of the very nature of the first cells. Synchronization of populations of non-living protocells through chemical communications may have been a mandatory step towards their emergence as populations of living cells and explain the large commonality of cell communication mechanisms among microorganisms, plants, and animals.
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titre: Allosteric interactions in the parathyroid hormone GPCR–arrestin complex formation
auteur: Lisa Clark, James Krieger, Alex White, Vasyl Bondarenko, Saifei Lei, Fei Fang, Ji Young Lee, Pemra Doruker, Thore Böttke, Frédéric Jean-Alphonse, Pei Tang, Thomas Gardella, Kunhong Xiao, Ieva Sutkeviciute, Irene Coin, Ivet Bahar, Jean-Pierre Vilardaga
article: Nature Chemical Biology, 2020, 16 (10), pp.1096-1104. ⟨10.1038/s41589-020-0567-0⟩
resume: Peptide ligands of class B G protein-coupled receptors (GPCRs) act via a two-step binding process, but the essential mechanisms that link their extracellular binding to intracellular receptor–arrestin interactions are not fully understood. Using NMR, crosslinking coupled to mass spectrometry, signaling experiments, and computational approaches on the parathyroid hormone (PTH) type 1 receptor (PTHR), we show that initial binding of the PTH C-terminal part constrains the conformation of the flexible PTH N-terminal signaling epitope before a second binding event occurs. A “hot spot” PTH residue, His9, that inserts into the PTHR transmembrane domain at this second step allosterically engages receptor–arrestin coupling. A conformational change in PTHR intracellular loop 3 permits favorable interactions with β-arrestin’s finger loop. These results unveil structural determinants for PTHR–arrestin complex formation and reveal that the two-step binding mechanism proceeds via cooperative fluctuations between ligand and receptor, which extend to other class B GPCRs.
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titre: 4C3 Human Monoclonal Antibody: A Proof of Concept for Non-pathogenic Proteinase 3 Anti-neutrophil Cytoplasmic Antibodies in Granulomatosis With Polyangiitis
auteur: Jérôme Granel, Roxane Lemoine, Eric Morello, Yann Gallais, Julie Mariot, Marion Drapeau, Astrid Musnier, Anne Poupon, Martine Pugnière, Seda Seren, Dalila Nouar, Valérie Gouilleux-Gruart, Herve Watier, Brice Korkmaz, Cyrille Hoarau
article: Frontiers in Immunology, 2020, 11, 17 p. ⟨10.3389/fimmu.2020.573040⟩
resume: Granulomatosis with polyangiitis (GPA) is a severe autoimmune vasculitis associated with the presence of anti-neutrophil cytoplasmic antibodies (ANCA) mainly targeting proteinase 3 (PR3), a neutrophilic serine proteinase.PR3-ANCA binding to membrane-bound PR3 on neutrophils induce their auto-immune activation responsible for vascular lesions. However, the correlation between PR3-ANCA level and disease activity remains inconsistent, suggesting the existence of non-pathogenic PR3-ANCA. In order to prove their existence, we immortalized B lymphocytes from blood samples of GPA patients in remission having persistent PR3-ANCA to isolate non-activating PR3-ANCA. We obtained for the first time a non-activating human IgG1κanti-PR3 monoclonal antibody (mAb) named 4C3. This new mAb binds soluble PR3 with a high affinity and membrane-bound PR3 on an epitope close to the PR3 hydrophobic patch and in the vicinity of the active site. 4C3 is able to bind FcγRIIA and FcγRIIIB and has a G2F glycosylation profile on asparagine 297. 4C3 did not induce activation of neutrophils and could inhibit human polyclonal PR3-ANCA-induced activation suggesting that 4C3 is non-pathogenic This characteristic relies on the recognized epitope on PR3 rather than to the Fc portion properties. The existence of non-pathogenic PR3-ANCA, which do not activate neutrophils, could explain the persistence of high PR3-ANCA levels in some GPA patients in remission and why PR3-ANCA would not predict relapse. Finally, these results offer promising perspectives particularly regarding the understanding of PR3-ANCA pathogenicity and the development of new diagnostic and therapeutic strategies in GPA
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titre: Research models and gene augmentation therapy for CRB1 retinal dystrophies
auteur: Nanda Boon, Jan Wijnholds, Lucie P. Pellissier
article: Frontiers in Neuroscience, 2020, 14, pp.1-13. ⟨10.3389/fnins.2020.00860⟩
resume: Retinitis pigmentosa (RP) and Leber congenital amaurosis (LCA) are inherited degenerative retinal dystrophies with vision loss that ultimately lead to blindness. Several genes have been shown to be involved in early onset retinal dystrophies, including CRB1 and RPE65. Gene therapy recently became available for young RP patients with variations in the RPE65 gene. Current research programs test adeno-associated viral gene augmentation or editing therapy vectors on various disease models mimicking the disease in patients. These include several animal and emerging human-derived models, such as human-induced pluripotent stem cell (hiPSC)-derived retinal organoids or hiPSC-derived retinal pigment epithelium (RPE), and human donor retinal explants. Variations in the CRB1 gene are a major cause for early onset autosomal recessive RP with patients suffering from visual impairment before their adolescence and for LCA with newborns experiencing severe visual impairment within the first months of life. These patients cannot benefit yet from an available gene therapy treatment. In this review, we will discuss the recent advances, advantages and disadvantages of different CRB1 human and animal retinal degeneration models. In addition, we will describe novel therapeutic tools that have been developed, which could potentially be used for retinal gene augmentation therapy for RP patients with variations in the CRB1 gene.
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titre: Mathematical modeling approaches of cellular endocrinology within the hypothalamo-pituitary-gonadal axis
auteur: Frédérique Clément, Pascale Crépieux, Romain Yvinec, Danielle Monniaux
article: Molecular and Cellular Endocrinology, 2020, 518, ⟨10.1016/j.mce.2020.110877⟩
resume: The reproductive neuroendocrine axis, or hypothalamo-pituitary-gonadal (HPG) axis, is a paragon of complex biological system involving numerous cell types, spread over several anatomical levels communicating through entangled endocrine feedback loops. The HPG axis exhibits remarkable dynamic behaviors on multiple time and space scales, which are an inexhaustible source of studies for mathematical and computational biology. In this review, we will describe a variety of modeling approaches of the HPG axis from a cellular endocrinology viewpoint. We will in particular investigate the questions raised by some of the most striking features of the HPG axis: (i) the pulsatile secretion of hypothalamic and pituitary hormones, and its counterpart, the cell signaling induced by frequency-encoded hormonal signals, and (ii) the dual, gametogenic and glandular function of the gonads, which relies on the tight control of the somatic cell populations ensuring the proper maturation and timely release of the germ cells.
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titre: Follicle-Stimulating Hormone (FSH) Action on Spermatogenesis: A Focus on Physiological and Therapeutic Roles
auteur: Daniele Santi, Pascale Crépieux, Eric Reiter, Giorgia Spaggiari, Giulia Brigante, Livio Casarini, Vincenzo Rochira, Manuela Simoni
article: Journal of Clinical Medicine, 2020, 9 (4), pp.1014. ⟨10.3390/jcm9041014⟩
resume: Background: Human reproduction is regulated by the combined action of the follicle-stimulating hormone (FSH) and the luteinizing hormone (LH) on the gonads. Although FSH is largely used in female reproduction, in particular in women attending assisted reproductive techniques to stimulate multi-follicular growth, its efficacy in men with idiopathic infertility is not clearly demonstrated. Indeed, whether FSH administration improves fertility in patients with hypogonadotropic hypogonadism, the therapeutic benefit in men presenting alterations in sperm production despite normal FSH serum levels is still unclear. In the present review, we evaluate the potential pharmacological benefits of FSH administration in clinical practice. Methods: This is a narrative review, describing the FSH physiological role in spermatogenesis and its potential therapeutic action in men. Results: The FSH role on male fertility is reviewed starting from the physiological control of spermatogenesis, throughout its mechanism of action in Sertoli cells, the genetic regulation of its action on spermatogenesis, until the therapeutic options available to improve sperm production. Conclusion: FSH administration in infertile men has potential benefits, although its action should be considered by evaluating its synergic action with testosterone, and well-controlled, powerful trials are required. Prospective studies and new compounds could be developed in the near future.
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titre: G q/11 -dependent regulation of endosomal cAMP generation by parathyroid hormone class B GPCR
auteur: Alex White, Frédéric Jean-Alphonse, Fei Fang, Karina Pena, Shi Liu, Gabriele König, Asuka Inoue, Despoina Aslanoglou, Samuel Gellman, Evi Kostenis, Kunhong Xiao, Jean-Pierre Vilardaga
article: Proceedings of the National Academy of Sciences of the United States of America, 2020, 117 (13), pp.7455-7460. ⟨10.1073/pnas.1918158117⟩
resume: cAMP production upon activation of Gsby G protein-coupled receptors has classically been considered to be plasma membrane-delimited, but a shift in this paradigm has occurred in recent years with the identification of several receptors that continue to signal from early endosomes after internalization. The molecular mech-anisms regulating this aspect of signaling remain incompletely understood. Here, we investigated the role of Gq/11 activation by the parathyroid hormone (PTH) type 1 receptor (PTHR) in mediating endosomal cAMP responses. Inhibition of Gq/11signaling by FR900359 markedly reduced the duration of PTH-induced cAMP production, and this effect was mimicked in cells lacking endogenous Gαq/11. We determined that modulation of cAMP generation by Gq/11 occurs at the level of the heterotrimeric G protein via liberation of cellsurface Gβγ subunits, which, in turn, act in a phosphoinositide-3kinase-dependent manner to promote the assembly of PTHR–βarrestin–Gβγsignaling complexes that mediate endosomal cAMP responses. These results unveil insights into the spatiotemporal reg-ulation of Gs-dependent cAMP signaling
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titre: FSH for the Treatment of Male Infertility
auteur: Livio Casarini, Pascale Crépieux, Eric Reiter, Clara Lazzaretti, Elia Paradiso, Vincenzo Rochira, Giulia Brigante, Daniele Santi, Manuela Simoni
article: International Journal of Molecular Sciences, 2020, 21 (7), pp.2270. ⟨10.3390/ijms21072270⟩
resume: Follicle-stimulating hormone (FSH) supports spermatogenesis acting via its receptor (FSHR), which activates trophic effects in gonadal Sertoli cells. These pathways are targeted by hormonal drugs used for clinical treatment of infertile men, mainly belonging to subgroups defined as hypogonadotropic hypogonadism or idiopathic infertility. While, in the first case, fertility may be efficiently restored by specific treatments, such as pulsatile gonadotropin releasing hormone (GnRH) or choriogonadotropin (hCG) alone or in combination with FSH, less is known about the efficacy of FSH in supporting the treatment of male idiopathic infertility. This review focuses on the role of FSH in the clinical approach to male reproduction, addressing the state-of-the-art from the little data available and discussing the pharmacological evidence. New compounds, such as allosteric ligands, dually active, chimeric gonadotropins and immunoglobulins, may represent interesting avenues for future personalized, pharmacological approaches to male infertility.
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titre: PTH hypersecretion triggered by a GABAB1 and Ca2+-sensing receptor heterocomplex in hyperparathyroidism
auteur: Wenhan Chang, Chia-Ling Tu, Frédéric Jean-Alphonse, Amanda Herberger, Zhiqiang Cheng, Jenna Hwong, Hanson Ho, Alfred Li, Dawei Wang, Hongda Liu, Alex White, Insoo Suh, Wen Shen, Quan-Yang Duh, Elham Khanafshar, Dolores Shoback, Kunhong Xiao, Jean-Pierre Vilardaga
article: Nature Metabolism, 2020, 2 (3), pp.243-255. ⟨10.1038/s42255-020-0175-z⟩
resume: Molecular mechanisms mediating tonic secretion of parathyroid hormone (PTH) in response to hypocalcaemia and hyperparathyroidism (HPT) are unclear. Here we demonstrate increased heterocomplex formation between the calcium-sensing receptor (CaSR) and metabotropic γ-aminobutyric acid (GABA) B1 receptor (GABAB1R) in hyperplastic parathyroid glands (PTGs) of patients with primary and secondary HPT. Targeted ablation of GABAB1R or glutamic acid decarboxylase 1 and 2 in PTGs produces hypocalcaemia and hypoparathyroidism, and prevents PTH hypersecretion in PTGs cultured from mouse models of hereditary HPT and dietary calcium-deficiency. Cobinding of the CaSR/GABAB1R complex by baclofen and high extracellular calcium blocks the coupling of heterotrimeric G-proteins to homomeric CaSRs in cultured cells and promotes PTH secretion in cultured mouse PTGs. These results combined with the ability of PTG to synthesize GABA support a critical autocrine action of GABA/GABAB1R in mediating tonic PTH secretion of PTGs and ascribe aberrant activities of CaSR/GABAB1R heteromer to HPT.
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titre: The orphan receptor GPR88 blunts the signaling of opioid receptors and multiple striatal GPCRs
auteur: Thibaut Laboute, Jorge Gandía, Lucie P. Pellissier, Yannick Corde, Florian Rebeillard, Maria Gallo, Christophe Gauthier, Audrey Léauté, Jorge Diaz, Anne Poupon, Brigitte L. Kieffer, Julie Le Merrer, Jérôme Aj Becker
article: eLife, 2020, 9, ⟨10.7554/eLife.50519⟩
resume: GPR88 is an orphan G protein-coupled receptor (GPCR) considered as a promising therapeutic target for neuropsychiatric disorders; its pharmacology, however, remains scarcely understood. Based on our previous report of increased delta opioid receptor activity in Gpr88 null mice, we investigated the impact of GPR88 co-expression on the signaling of opioid receptors in vitro and revealed that GPR88 inhibits the activation of both their G protein- and beta-arrestin-dependent signaling pathways. In Gpr88 knockout mice, morphine-induced locomotor sensitization, withdrawal and supra-spinal analgesia were facilitated, consistent with a tonic inhibitory action of GPR88 on mOR signaling. We then explored GPR88 interactions with more striatal versus non-neuronal GPCRs, and revealed that GPR88 can decrease the G protein-dependent signaling of most receptors in close proximity, but impedes beta-arrestin recruitment by all receptors tested. Our study unravels an unsuspected buffering role of GPR88 expression on GPCR signaling, with intriguing consequences for opioid and striatal functions.
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titre: Multiscale population dynamics in reproductive biology: singular perturbation reduction in deterministic and stochastic models
auteur: Celine Bonnet, Keltoum Chahour, Frédérique Clément, Marie Postel, Romain Yvinec
article: ESAIM: Proceedings and Surveys, 2020, 67, pp.72-99. ⟨10.1051/proc/202067006⟩
resume: In this study, we describe different modeling approaches for ovarian follicle population dynamics, based on either ordinary (ODE), partial (PDE) or stochastic (SDE) differential equations, and accounting for interactions between follicles. We put a special focus on representing the populationlevel feedback exerted by growing ovarian follicles onto the activation of quiescent follicles. We take advantage of the timescale difference existing between the growth and activation processes to apply model reduction techniques in the framework of singular perturbations. We first study the linear versions of the models to derive theoretical results on the convergence to the limit models. In the nonlinear cases, we provide detailed numerical evidence of convergence to the limit behavior. We reproduce the main semi-quantitative features characterizing the ovarian follicle pool, namely a bimodal distribution of the whole population, and a slope break in the decay of the quiescent pool with aging.
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titre: Pleotropism of gonadotropin action
auteur: Manuela Simoni, Elia Paradiso, Véronique Lockhart, Eric Reiter, Livio Casarini, Lucie P. Pellissier, Pascale Crépieux
article: Le Studium Multidisciplinary Journal, 2020, 4, pp.1-7. ⟨10.34846/le-studium.194.02.fr.03-2020⟩
resume: Evidence exists that the gonadotropins LH and FSH can substitute to each other under certain circumstances, in addition to the fact that they can act together in granulosa cells. The aim of this study is to investigate how the two human gonadotropins influence each other in granulosa cells expressing both receptors, or by co-culturing cells expressing either the LHCGR or the FSHR (as a model granulosa/theca interaction). Plasmids encoding the c-myc-tagged-LHCGR and the FLAG-tagged FSHR under the control of an inducible coumermycin-responsive or doxycycline-responsive promoter, respectively were produced. These plasmids were used to permanently transfect human granulosa cell-derived KGN cells and HEK293 cells. The following cell lines were obtained and partially characterized: #1 c-myc-tagged-LHCGR-KGN; #2 FLAG-tagged FSHR_HEK293; #3 FLAG-tagged FSHR-KGN; #4 Double, c-myc-tagged-LHCGR and FLAG-tagged FSHR-KGN. After induction of receptor expression, the cell lines #1 and #2 and #3 responded to hCG and FSH stimulation, respectively by producing cAMP. Receptor expression was demonstrated by RT-PCR and flow cytometry. The characterization of the cell line #4 is ongoing. These cell lines are now available for the study of cell signaling and steroid synthesis, as well as in silico modeling, to gain insight into the dynamics of the intertwined cell response to FSH and LH in granulosa cells. These experiments will continue in parallel in both laboratories involved. Our cell lines represent new, very valuable instruments for the study of molecular pharmacology of FSH and LH, in order to improve infertility treatment, (multi)follicular growth for assisted reproduction, ovulation and spermatogenesis.
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