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Morisset-Lopez Séverine


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Publications

2017   Références trouvées : 3

Nadim, W. D. Simion, V. Benedetti, H. Pichon, C. Baril, P. Morisset-Lopez, S.  (2017)

MicroRNAs in Neurocognitive Dysfunctions : New Molecular Targets for Pharmacological Treatments ?

Current neuropharmacology (2017) 15 (2) 260-275
BACKGROUND : Neurodegenerative and cognitive disorders are multifactorial diseases (i.e., involving neurodevelopmental, genetic, age or environmental factors) characterized by an abnormal development that affects neuronal function and integrity. Recently, an increasing number of studies revealed that the dysregulation of microRNAs (miRNAs) may be involved in the etiology of cognitive disorders as Alzheimer, Parkinson, and Huntington's diseases, Schizophrenia and Autism spectrum disorders. METHODS : From an extensive search in bibliographic databases of peer-reviewed research literature, we identified relevant published studies related to specific key words such as memory, cognition, neurodegenerative disorders, neurogenesis and miRNA. We then analysed, evaluated and summerized scientific evidences derived from these studies. RESULTS : We first briefly summarize the basic molecular events involved in memory, a process inherent to cognitive disease, and then describe the role of miRNAs in neurodevelopment, synaptic plasticity and memory. Secondly, we provide an overview of the impact of miRNA dysregulation in the pathogenesis of different neurocognitive disorders, and lastly discuss the feasibility of miRNA-based therapeutics in the treatment of these disorders. CONCLUSION : This review highlights the molecular basis of neurodegenerative and cognitive disorders by focusing on the impact of miRNAs dysregulation in these pathological phenotypes. Altogether, the published reports suggest that miRNAs-based therapy could be a viable therapeutic alternative to current treatment options in the future.

BACKGROUND : Neurodegenerative and cognitive disorders are multifactorial diseases (i.e., involving neurodevelopmental, genetic, age or environmental factors) characterized by an abnormal development that affects neuronal function and integrity. Recently, an increasing number of studies revealed that the dysregulation of microRNAs (miRNAs) may be involved in the etiology of cognitive disorders as Alzheimer, Parkinson, and Huntington’s diseases, Schizophrenia and Autism spectrum disorders. METHODS : From an extensive search in bibliographic databases of peer-reviewed research literature, we identified relevant published studies related to specific key words such as memory, cognition, neurodegenerative disorders, neurogenesis and miRNA. We then analysed, evaluated and summerized scientific evidences derived from these studies. RESULTS : We first briefly summarize the basic molecular events involved in memory, a process inherent to cognitive disease, and then describe the role of miRNAs in neurodevelopment, synaptic plasticity and memory. Secondly, we provide an overview of the impact of miRNA dysregulation in the pathogenesis of different neurocognitive disorders, and lastly discuss the feasibility of miRNA-based therapeutics in the treatment of these disorders. CONCLUSION : This review highlights the molecular basis of neurodegenerative and cognitive disorders by focusing on the impact of miRNAs dysregulation in these pathological phenotypes. Altogether, the published reports suggest that miRNAs-based therapy could be a viable therapeutic alternative to current treatment options in the future.

Deraredj Nadim, W., Simion, V., Bénédetti, H., Pichon, C., Baril, P. and Morisset-Lopez, S.  (2017)

MicroRNAs in Neurocognitive Dysfunctions : New Molecular Targets for Pharmacological Treatments ?

Current Neuropharmacology (2017) 15 (2) 260-275
BACKGROUND : Neurodegenerative and cognitive disorders are multifactorial diseases (i.e., involving neurodevelopmental, genetic, age or environmental factors) characterized by an abnormal development that affects neuronal function and integrity. Recently, an increasing number of studies revealed that the dysregulation of microRNAs (miRNAs) may be involved in the etiology of cognitive disorders as Alzheimer, Parkinson, and Huntington's diseases, Schizophrenia and Autism spectrum disorders.

METHODS : From an extensive search in bibliographic databases of peer-reviewed research literature, we identified relevant published studies related to specific key words such as memory, cognition, neurodegenerative disorders, neurogenesis and miRNA. We then analysed, evaluated and summerized scientific evidences derived from these studies.

RESULTS : We first briefly summarize the basic molecular events involved in memory, a process inherent to cognitive disease, and then describe the role of miRNAs in neurodevelopment, synaptic plasticity and memory. Secondly, we provide an overview of the impact of miRNA dysregulation in the pathogenesis of different neurocognitive disorders, and lastly discuss the feasibility of miRNA-based therapeutics in the treatment of these disorders.

CONCLUSION : This review highlights the molecular basis of neurodegenerative and cognitive disorders by focusing on the impact of miRNAs dysregulation in these pathological phenotypes. Altogether, the published reports suggest that miRNAs-based therapy could be a viable therapeutic alternative to current treatment options in the future.

BACKGROUND : Neurodegenerative and cognitive disorders are multifactorial diseases (i.e., involving neurodevelopmental, genetic, age or environmental factors) characterized by an abnormal development that affects neuronal function and integrity. Recently, an increasing number of studies revealed that the dysregulation of microRNAs (miRNAs) may be involved in the etiology of cognitive disorders as Alzheimer, Parkinson, and Huntington’s diseases, Schizophrenia and Autism spectrum disorders.
METHODS : From an extensive search in bibliographic databases of peer-reviewed research literature, we identified relevant published studies related to specific key words such as memory, cognition, neurodegenerative disorders, neurogenesis and miRNA. We then analysed, evaluated and summerized scientific evidences derived from these studies.
RESULTS : We first briefly summarize the basic molecular events involved in memory, a process inherent to cognitive disease, and then describe the role of miRNAs in neurodevelopment, synaptic plasticity and memory. Secondly, we provide an overview of the impact of miRNA dysregulation in the pathogenesis of different neurocognitive disorders, and lastly discuss the feasibility of miRNA-based therapeutics in the treatment of these disorders.
CONCLUSION : This review highlights the molecular basis of neurodegenerative and cognitive disorders by focusing on the impact of miRNAs dysregulation in these pathological phenotypes. Altogether, the published reports suggest that miRNAs-based therapy could be a viable therapeutic alternative to current treatment options in the future.

Simion, V., Deraredj Nadim, W., Benedetti, H., Pichon, C., Morisset-Lopez, S. and Baril, P.  (2017)

Pharmacomodulation of microRNA expression in neurocognitive diseases : obstacles and future opportunities

Current Neuropharmacology (2017) 15 (2) 276-290
Given the importance of microRNAs (miRNAs) in modulating brain functions and their implications in neurocognitive disorders there are currently significant efforts devoted in the field of miRNA-based therapeutics to correct and/or to treat these brain diseases. The observation that miRNA 29a/b-1 cluster, miRNA 10b and miRNA 7, for instance, are frequently deregulated in the brains of patients with neurocognitive diseases and in animal models of Alzheimer, Huntington's and Parkinson's diseases, suggest that correction of miRNA expression using agonist or antagonist miRNA oligonucleotides might be a promising approach to correct or even to cure such diseases. The encouraging results from recent clinical trials allow envisioning that pharmacological approaches based on miRNAs might, in a near future, reach the requirements for successful therapeutic outcomes and will improve the healthcare of patients with brain injuries or disorders. This review will focus on the current strategies used to modulate pharmacological function of miRNA using chemically modified oligonucleotides. We will then review the recent literature on strategies to improve nucleic acid delivery across the blood-brain barrier which remains a severe obstacle to the widespread application of miRNA therapeutics to treat brain diseases. Finally, we provide a state-of-art of current preclinical research performed in animal models for the treatment of neurocognitive disorders using miRNA as therapeutic agents and discuss future developments of miRNA therapeutics.

Given the importance of microRNAs (miRNAs) in modulating brain functions and their implications in neurocognitive disorders there are currently significant efforts devoted in the field of miRNA-based therapeutics to correct and/or to treat these brain diseases. The observation that miRNA 29a/b-1 cluster, miRNA 10b and miRNA 7, for instance, are frequently deregulated in the brains of patients with neurocognitive diseases and in animal models of Alzheimer, Huntington’s and Parkinson’s diseases, suggest that correction of miRNA expression using agonist or antagonist miRNA oligonucleotides might be a promising approach to correct or even to cure such diseases. The encouraging results from recent clinical trials allow envisioning that pharmacological approaches based on miRNAs might, in a near future, reach the requirements for successful therapeutic outcomes and will improve the healthcare of patients with brain injuries or disorders. This review will focus on the current strategies used to modulate pharmacological function of miRNA using chemically modified oligonucleotides. We will then review the recent literature on strategies to improve nucleic acid delivery across the blood-brain barrier which remains a severe obstacle to the widespread application of miRNA therapeutics to treat brain diseases. Finally, we provide a state-of-art of current preclinical research performed in animal models for the treatment of neurocognitive disorders using miRNA as therapeutic agents and discuss future developments of miRNA therapeutics.


2016   Références trouvées : 2

Deraredj Nadim W., Chaumont-Dubel S., Madouri F., Cobret L., De Tauzia M.-L., Zajdel P., Bénédetti H., Marin P. and Morisset-Lopez S.  (2016)

Physical Interaction between Neurofibromin and Serotonin 5-HT6 Receptor Promotes Receptor Constitutive Activity

Proc Natl Acad Sci U S A (2016) 113 (43) 12310-12315 - doi : 10.1073/pnas.1600914113
Active G protein-coupled receptor (GPCR) conformations not only are promoted by agonists but also occur in their absence, leading to constitutive activity. Association of GPCRs with intracellular protein partners might be one of the mechanisms underlying GPCR constitutive activity. Here, we show that serotonin 5 hydroxytryptamine 6 (5-HT6) receptor constitutively activates the Gs/adenylyl cyclase pathway in various cell types, including neurons. Constitutive activity is strongly reduced by silencing expression of the Ras-GTPase activating protein (Ras-GAP) neurofibromin, a 5-HT6 receptor partner. Neurofibromin is a multidomain protein encoded by the NF1 gene, the mutation of which causes Neurofibromatosis type 1 (NF1), a genetic disorder characterized by multiple benign and malignant nervous system tumors and cognitive deficits. Disrupting association of 5-HT6 receptor with neurofibromin Pleckstrin Homology (PH) domain also inhibits receptor constitutive activity, and PH domain expression rescues 5-HT6 receptor-operated cAMP signaling in neurofibromin-deficient cells. Furthermore, PH domains carrying mutations identified in NF1 patients that prevent interaction with the 5-HT6 receptor fail to rescue receptor constitutive activity in neurofibromin-depleted cells. Further supporting a role of neurofibromin in agonist-independent Gs signaling elicited by native receptors, the phosphorylation of cAMP-responsive element-binding protein (CREB) is strongly decreased in prefrontal cortex of Nf1+/− mice compared with WT mice. Moreover, systemic administration of a 5-HT6 receptor inverse agonist reduces CREB phosphorylation in prefrontal cortex of WT mice but not Nf1+/− mice. Collectively, these findings suggest that disrupting 5-HT6 receptor–neurofibromin interaction prevents agonist-independent 5-HT6 receptor-operated cAMP signaling in prefrontal cortex, an effect that might underlie neuronal abnormalities in NF1 patients.

Active G protein-coupled receptor (GPCR) conformations not only are promoted by agonists but also occur in their absence, leading to constitutive activity. Association of GPCRs with intracellular protein partners might be one of the mechanisms underlying GPCR constitutive activity. Here, we show that serotonin 5 hydroxytryptamine 6 (5-HT6) receptor constitutively activates the Gs/adenylyl cyclase pathway in various cell types, including neurons. Constitutive activity is strongly reduced by silencing expression of the Ras-GTPase activating protein (Ras-GAP) neurofibromin, a 5-HT6 receptor partner. Neurofibromin is a multidomain protein encoded by the NF1 gene, the mutation of which causes Neurofibromatosis type 1 (NF1), a genetic disorder characterized by multiple benign and malignant nervous system tumors and cognitive deficits. Disrupting association of 5-HT6 receptor with neurofibromin Pleckstrin Homology (PH) domain also inhibits receptor constitutive activity, and PH domain expression rescues 5-HT6 receptor-operated cAMP signaling in neurofibromin-deficient cells. Furthermore, PH domains carrying mutations identified in NF1 patients that prevent interaction with the 5-HT6 receptor fail to rescue receptor constitutive activity in neurofibromin-depleted cells. Further supporting a role of neurofibromin in agonist-independent Gs signaling elicited by native receptors, the phosphorylation of cAMP-responsive element-binding protein (CREB) is strongly decreased in prefrontal cortex of Nf1+/− mice compared with WT mice. Moreover, systemic administration of a 5-HT6 receptor inverse agonist reduces CREB phosphorylation in prefrontal cortex of WT mice but not Nf1+/− mice. Collectively, these findings suggest that disrupting 5-HT6 receptor–neurofibromin interaction prevents agonist-independent 5-HT6 receptor-operated cAMP signaling in prefrontal cortex, an effect that might underlie neuronal abnormalities in NF1 patients.

Chebani, Y. Marion, C. Zizzari, P. Chettab, K. Pastor, M. Korostelev, M. Geny, D. Epelbaum, J. Tolle, V. Morisset-Lopez, S. and Pantel, J.  (2016)

Enhanced responsiveness of Ghsr Q343X rats to ghrelin results in enhanced adiposity without increased appetite

Science signaling (2016) 9 (424) ra39 - doi : 10.1126/scisignal.aae0374
The ability of the gut hormone ghrelin to promote positive energy balance is mediated by the growth hormone secretagogue receptor (GHSR). GHSR is a G protein-coupled receptor (GPCR) that is found centrally and peripherally and that can signal in a ligand-independent manner basally or when heterodimerized with other GPCRs. However, currentGhsrknockout models cannot dissect ghrelin-dependent and ghrelin-independent signaling, precluding assessment of the physiological importance of these signaling pathways. An animal model carrying aGhsrmutation that preserves GHSR cell surface abundance, but selectively alters GHSR signaling, would be a useful tool to decipher GHSR signaling in vivo. We used rats with theGhsr(Q343X)mutation (Ghsr(M/M)), which is predicted to delete the distal part of the GHSR carboxyl-terminal tail, a domain critical for the signal termination processes of receptor internalization and beta-arrestin recruitment. In cells, the GHSR-Q343X mutant showed enhanced ligand-induced G protein-dependent signaling and blunted activity of processes involved in GPCR signal termination.Ghsr(M/M)rats displayed enhanced responses to submaximal doses of ghrelin or GHSR agonist. Moreover,Ghsr(M/M)rats had a more stable body weight under caloric restriction, a condition that increases endogenous ghrelin tone, whereas under standard housing conditions,Ghsr(M/M)rats showed increased body weight and adiposity and reduced glucose tolerance. Overall, our data stress the physiological role of the distal domain of GHSR carboxyl terminus as a suppressor of ghrelin sensitivity, and we propose using theGhsr(M/M)rat as a physiological model of gain of function inGhsrto identify treatments for obesity-related conditions.

The ability of the gut hormone ghrelin to promote positive energy balance is mediated by the growth hormone secretagogue receptor (GHSR). GHSR is a G protein-coupled receptor (GPCR) that is found centrally and peripherally and that can signal in a ligand-independent manner basally or when heterodimerized with other GPCRs. However, currentGhsrknockout models cannot dissect ghrelin-dependent and ghrelin-independent signaling, precluding assessment of the physiological importance of these signaling pathways. An animal model carrying aGhsrmutation that preserves GHSR cell surface abundance, but selectively alters GHSR signaling, would be a useful tool to decipher GHSR signaling in vivo. We used rats with theGhsr(Q343X)mutation (Ghsr(M/M)), which is predicted to delete the distal part of the GHSR carboxyl-terminal tail, a domain critical for the signal termination processes of receptor internalization and beta-arrestin recruitment. In cells, the GHSR-Q343X mutant showed enhanced ligand-induced G protein-dependent signaling and blunted activity of processes involved in GPCR signal termination.Ghsr(M/M)rats displayed enhanced responses to submaximal doses of ghrelin or GHSR agonist. Moreover,Ghsr(M/M)rats had a more stable body weight under caloric restriction, a condition that increases endogenous ghrelin tone, whereas under standard housing conditions,Ghsr(M/M)rats showed increased body weight and adiposity and reduced glucose tolerance. Overall, our data stress the physiological role of the distal domain of GHSR carboxyl terminus as a suppressor of ghrelin sensitivity, and we propose using theGhsr(M/M)rat as a physiological model of gain of function inGhsrto identify treatments for obesity-related conditions.


2015   Références trouvées : 2

Deau E., Robin E., Voinea R., Percina N., Satala G., Finaru A. L., Chartier A., Tamagnan G., Alagille D., Bojarski A. J., Morisset-Lopez S., Suzenet F. and Guillaumet G.  (2015)

Rational Design, Pharmacomodulation, and Synthesis of Dual 5-Hydroxytryptamine 7 (5-HT7)/5-Hydroxytryptamine 2A (5-HT2A) Receptor Antagonists and Evaluation by F-18 -PET Imaging in a Primate Brain

Journal of Medicinal Chemistry (2015) 58 (20) 8066-8096 - doi : 10.1021/acs.jmedchem.5b00874
We report the synthesis of 46 tertiary amine-bearing N-alkylated benzo[d]imidazol-2(3H)-ones, imidazo-[4,5-b]pyridin-2(3H)-ones, irnidazo[4,5-c]pyridin-2(3H)-ones, benzo [d] oxazol-2 (3H) -ones, oxazolo [4,5- b]pyridin-2(3H)-ones and N,N'-dialkylate d benzo [d] imidazol-2 (3H)-ones. These compounds were evaluated against 5-HT7R, 5-HT2AR, 5-HT1AR, and 5-HT6R as potent dual 5-HT7/5-HT2A serotonin receptors ligands. A thorough study of the structure-activity relationship of the aromatic rings and their substituents, the alkyl chain length and the tertiary amine was conducted. 1-(4-(4-(4-Fluorobenzoyl)piperidin-1-yl)butyl)-1H-benzo[d]imidazol-2(3H)-one (79) and 1-(6-(4-(4-fluorobenzoyDpiperidin-1-yOhexyl)-1H-benzo[d]imidazol-2(3H)-one (81) were identified as full antagonist ligands on cyclic adenosine monophosphate (cAMP, K-B = 4.9 and 5.9 nM, respectively) and inositol monophosphate (IP1, K-B = 0.6 and 16 nM, respectively) signaling pathways of 5-HT7R and 5-HT2AR. Both antagonists crossed the blood-brain barrier as evaluated with [F-18] radiolabeled compounds [F-18]79 and [F-18]81 in a primate's central nervous system using positron emission tomography. Both radioligands showed standard uptake values ranging from 0.8 to 1.1, a good plasmatic stability, and a distribution consistent with 5-HT7R and 5-HT2AR in the CNS.

We report the synthesis of 46 tertiary amine-bearing N-alkylated benzo[d]imidazol-2(3H)-ones, imidazo-[4,5-b]pyridin-2(3H)-ones, irnidazo[4,5-c]pyridin-2(3H)-ones, benzo [d] oxazol-2 (3H) -ones, oxazolo [4,5- b]pyridin-2(3H)-ones and N,N’-dialkylate d benzo [d] imidazol-2 (3H)-ones. These compounds were evaluated against 5-HT7R, 5-HT2AR, 5-HT1AR, and 5-HT6R as potent dual 5-HT7/5-HT2A serotonin receptors ligands. A thorough study of the structure-activity relationship of the aromatic rings and their substituents, the alkyl chain length and the tertiary amine was conducted. 1-(4-(4-(4-Fluorobenzoyl)piperidin-1-yl)butyl)-1H-benzo[d]imidazol-2(3H)-one (79) and 1-(6-(4-(4-fluorobenzoyDpiperidin-1-yOhexyl)-1H-benzo[d]imidazol-2(3H)-one (81) were identified as full antagonist ligands on cyclic adenosine monophosphate (cAMP, K-B = 4.9 and 5.9 nM, respectively) and inositol monophosphate (IP1, K-B = 0.6 and 16 nM, respectively) signaling pathways of 5-HT7R and 5-HT2AR. Both antagonists crossed the blood-brain barrier as evaluated with [F-18] radiolabeled compounds [F-18]79 and [F-18]81 in a primate’s central nervous system using positron emission tomography. Both radioligands showed standard uptake values ranging from 0.8 to 1.1, a good plasmatic stability, and a distribution consistent with 5-HT7R and 5-HT2AR in the CNS.

Cobret, L., De Tauzia, M.L., Ferent, J., Traiffort, E., Hénaoui, I., Godin, F., Kellenberger, E., Rognan, D., Pantel, J., Bénédetti, H. and Morisset-Lopez, S.  (2015)

Targeting the cis-dimerization of LINGO-1 with low MW compounds affects its downstream signalling

British Journal of Pharmacology 172 (3) 841-856 - doi : 10.1111/bph.12945
Background and Purpose The transmembrane protein LINGO-1 is a negative regulator in the nervous system mainly affecting axonal regeneration, neuronal survival, oligodendrocyte differentiation and myelination. However, the molecular mechanisms regulating its functions are poorly understood. In the present study, we investigated the formation and the role of LINGO-1 cis-dimers in the regulation of its biological activity. Experimental Approach LINGO-1 homodimers were identified in both HEK293 and SH-SY5Y cells using co-immunoprecipitation experiments and BRET saturation analysis. We performed a hypothesis-driven screen for identification of small-molecule protein–protein interaction modulators of LINGO-1 using a BRET-based assay, adapted for screening. The compound identified was further assessed for effects on LINGO-1 downstream signalling pathways using Western blotting analysis and AlphaScreen technology. Key Results LINGO-1 was present as homodimers in primary neuronal cultures. LINGO-1 interacted homotypically in cis-orientation and LINGO-1 cis-dimers were formed early during LINGO-1 biosynthesis. A BRET-based assay allowed us to identify phenoxybenzamine as the first conformational modulator of LINGO-1 dimers. In HEK-293 cells, phenoxybenzamine was a positive modulator of LINGO-1 function, increasing the LINGO-1-mediated inhibition of EGF receptor signalling and Erk phosphorylation. Conclusions and Implications Our data suggest that LINGO-1 forms constitutive cis-dimers at the plasma membrane and that low MW compounds affecting the conformational state of these dimers can regulate LINGO-1 downstream signalling pathways. We propose that targeting the LINGO-1 dimerization interface opens a new pharmacological approach to the modulation of its function and provides a new strategy for drug discovery.

Background and Purpose The transmembrane protein LINGO-1 is a negative regulator in the nervous system mainly affecting axonal regeneration, neuronal survival, oligodendrocyte differentiation and myelination. However, the molecular mechanisms regulating its functions are poorly understood. In the present study, we investigated the formation and the role of LINGO-1 cis-dimers in the regulation of its biological activity. Experimental Approach LINGO-1 homodimers were identified in both HEK293 and SH-SY5Y cells using co-immunoprecipitation experiments and BRET saturation analysis. We performed a hypothesis-driven screen for identification of small-molecule protein–protein interaction modulators of LINGO-1 using a BRET-based assay, adapted for screening. The compound identified was further assessed for effects on LINGO-1 downstream signalling pathways using Western blotting analysis and AlphaScreen technology. Key Results LINGO-1 was present as homodimers in primary neuronal cultures. LINGO-1 interacted homotypically in cis-orientation and LINGO-1 cis-dimers were formed early during LINGO-1 biosynthesis. A BRET-based assay allowed us to identify phenoxybenzamine as the first conformational modulator of LINGO-1 dimers. In HEK-293 cells, phenoxybenzamine was a positive modulator of LINGO-1 function, increasing the LINGO-1-mediated inhibition of EGF receptor signalling and Erk phosphorylation. Conclusions and Implications Our data suggest that LINGO-1 forms constitutive cis-dimers at the plasma membrane and that low MW compounds affecting the conformational state of these dimers can regulate LINGO-1 downstream signalling pathways. We propose that targeting the LINGO-1 dimerization interface opens a new pharmacological approach to the modulation of its function and provides a new strategy for drug discovery.


2014   Références trouvées : 1

Duhr, F., Déléris, P., Raynaud, F., Séveno, M., Morisset-Lopez, S., Mannoury la Cour, C., Millan, M.J., Bockaert, J., Marin, P. and Chaumont-Dubel, S.  (2014)

Cdk5 induces constitutive activation of 5-HT6 receptors to promote neurite growth

Nature Chemical Biology (2014) 10 (7) 590-597 - doi : 10.1038/nchembio.1547
The serotonin6 receptor (5-HT6R) is a promising target for treating cognitive deficits of schizophrenia often linked to alterations of neuronal development. This receptor controls neurodevelopmental processes, but the signaling mechanisms involved remain poorly understood. Using a proteomic strategy, we show that 5-HT6Rs constitutively interact with cyclin-dependent kinase 5 (Cdk5). Expression of 5-HT6Rs in NG108-15 cells induced neurite growth and expression of voltage-gated Ca2+ channels, two hallmarks of neuronal differentiation. 5-HT6R–elicited neurite growth was agonist independent and prevented by the 5-HT6R antagonist SB258585, which behaved as an inverse agonist. Moreover, it required receptor phosphorylation at Ser350 by Cdk5 and Cdc42 activity. Supporting a role of native 5-HT6Rs in neuronal differentiation, neurite growth of primary neurons was reduced by SB258585, by silencing 5-HT6R expression or by mutating Ser350 into alanine. These results reveal a functional interplay between Cdk5 and a G protein–coupled receptor to control neuronal differentiation.

The serotonin6 receptor (5-HT6R) is a promising target for treating cognitive deficits of schizophrenia often linked to alterations of neuronal development. This receptor controls neurodevelopmental processes, but the signaling mechanisms involved remain poorly understood. Using a proteomic strategy, we show that 5-HT6Rs constitutively interact with cyclin-dependent kinase 5 (Cdk5). Expression of 5-HT6Rs in NG108-15 cells induced neurite growth and expression of voltage-gated Ca2+ channels, two hallmarks of neuronal differentiation. 5-HT6R–elicited neurite growth was agonist independent and prevented by the 5-HT6R antagonist SB258585, which behaved as an inverse agonist. Moreover, it required receptor phosphorylation at Ser350 by Cdk5 and Cdc42 activity. Supporting a role of native 5-HT6Rs in neuronal differentiation, neurite growth of primary neurons was reduced by SB258585, by silencing 5-HT6R expression or by mutating Ser350 into alanine. These results reveal a functional interplay between Cdk5 and a G protein–coupled receptor to control neuronal differentiation.


2012   Références trouvées : 1

Godin, F., Villette, S., Vallée, B., Doudeau, M., Morisset-Lopez, S., Ardourel, M., Hevor, T., Pichon, C. and Bénédetti, B.  (2012)

A fraction of neurofibromin interacts with PML bodies in the nucleus of the CCF astrocytoma cell line

Biochemical and Biophysical Research Communications 418 (4) 689-694
Neurofibromatosis type 1 is a common genetic disease that causes nervous system tumors, and cognitive deficits. It is due to mutations within the NF1 gene, which encodes the Nf1 protein. Nf1 has been shown to be involved in the regulation of Ras, cAMP and actin cytoskeleton dynamics. In this study, using immunofluorescence experiments, we have shown a partial nuclear localization of Nf1 in the astrocytoma cell line : CCF and we have demonstrated that Nf1 partially colocalizes with PML (promyelocytic leukemia) nuclear bodies. A direct interaction between Nf1 and the multiprotein complex has further been demonstrated using ‘‘in situ’’ proximity ligation assay (PLA).

Neurofibromatosis type 1 is a common genetic disease that causes nervous system tumors, and cognitive deficits. It is due to mutations within the NF1 gene, which encodes the Nf1 protein. Nf1 has been shown to be involved in the regulation of Ras, cAMP and actin cytoskeleton dynamics. In this study, using immunofluorescence experiments, we have shown a partial nuclear localization of Nf1 in the astrocytoma cell line : CCF and we have demonstrated that Nf1 partially colocalizes with PML (promyelocytic leukemia) nuclear bodies. A direct interaction between Nf1 and the multiprotein complex has further been demonstrated using ‘‘in situ’’ proximity ligation assay (PLA).


2010   Références trouvées : 3

Picard M. Morisset S., Cloix J. F., Bizot J. C., Guerin M., Beneteau V., Guillaumet G. and Hevor T. K.  (2010)

Pharmacological, neurochemical, and behavioral profile of JB-788, a new 5-HT1A agonist

Neuroscience 169 (3) 1337-1346 - doi : 10.1016/j.neuroscience.2010.05.040
A novel pyridine derivative, 8-4-[(6-methoxy-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-3-ylmethyl)-amino]-butyl -8-aza-spiro[4.5]decane-7,9-dione hydrochloride, termed JB-788, was designed to selectively target 5-HT(1A) receptors. In the present study, the pharmacological profile of JB-788 was characterized in vitro using radioligands binding tests and in vivo using neurochemical and behavioural experiments. JB-788 bound tightly to human 5-HT(1A) receptor expressed in human embryonic kidney 293 (HEK-293) cells with a K(i) value of 0.8 nM. Its binding affinity is in the same range as that observed for the (+/-)8-OH-DPAT, a reference 5HT(1A) agonist compound. Notably, JB-788 only bound weakly to 5-HT(1B) or 5-HT(2A) receptors and moreover the drug displayed only weak or indetectable binding to muscarinic, alpha(2), beta(1) and beta(2) adrenergic receptors, or dopaminergic D(1) receptors. JB-788 was found to display substantial binding affinity for dopaminergic D(2) receptors and, to a lesser extend to alpha(1) adrenoreceptors. JB-788 dose-dependently decreased forskolin-induced cAMP accumulation in HEK cells expressing human 5-HT(1A), thus acting as a potent 5-HT(1A) receptor agonist (E(max.) 75%, EC(50) 3.5 nM). JB-788 did not exhibit any D(2) receptor agonism but progressively inhibited the effects of quinpirole, a D(2) receptor agonist, in the cAMP accumulation test with a K(i) value of 250 nM. JB-788 induced a weak change in cAMP levels in mouse brain but, like some antipsychotics, transiently increased glycogen contents in various brain regions. Behavioral effects were investigated in mice using the elevated plus-maze. JB-788 was found to increase the time duration spent by animals in anxiogenic situations. Locomotor hyperactivity induced by methamphetamine in mouse, a model of antipsychotic activity, was dose-dependently inhibited by JB-788. Altogether, these results suggest that JB-788 displays pharmacological properties, which could be of interest in the area of anxiolytic and antipsychotic drugs.

A novel pyridine derivative, 8-4-[(6-methoxy-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-3-ylmethyl)-amino]-butyl -8-aza-spiro[4.5]decane-7,9-dione hydrochloride, termed JB-788, was designed to selectively target 5-HT(1A) receptors. In the present study, the pharmacological profile of JB-788 was characterized in vitro using radioligands binding tests and in vivo using neurochemical and behavioural experiments. JB-788 bound tightly to human 5-HT(1A) receptor expressed in human embryonic kidney 293 (HEK-293) cells with a K(i) value of 0.8 nM. Its binding affinity is in the same range as that observed for the (+/-)8-OH-DPAT, a reference 5HT(1A) agonist compound. Notably, JB-788 only bound weakly to 5-HT(1B) or 5-HT(2A) receptors and moreover the drug displayed only weak or indetectable binding to muscarinic, alpha(2), beta(1) and beta(2) adrenergic receptors, or dopaminergic D(1) receptors. JB-788 was found to display substantial binding affinity for dopaminergic D(2) receptors and, to a lesser extend to alpha(1) adrenoreceptors. JB-788 dose-dependently decreased forskolin-induced cAMP accumulation in HEK cells expressing human 5-HT(1A), thus acting as a potent 5-HT(1A) receptor agonist (E(max.) 75%, EC(50) 3.5 nM). JB-788 did not exhibit any D(2) receptor agonism but progressively inhibited the effects of quinpirole, a D(2) receptor agonist, in the cAMP accumulation test with a K(i) value of 250 nM. JB-788 induced a weak change in cAMP levels in mouse brain but, like some antipsychotics, transiently increased glycogen contents in various brain regions. Behavioral effects were investigated in mice using the elevated plus-maze. JB-788 was found to increase the time duration spent by animals in anxiogenic situations. Locomotor hyperactivity induced by methamphetamine in mouse, a model of antipsychotic activity, was dose-dependently inhibited by JB-788. Altogether, these results suggest that JB-788 displays pharmacological properties, which could be of interest in the area of anxiolytic and antipsychotic drugs.

Motawaj M., Burban A., Davenas E., Gbahou F., Faucard R., Morisset S. and Arrang J.M.  (2010)

Le système histaminergique : une cible pour de nouveaux traitements des déficits cognitifs - The Histaminergic System : a Target for Innovative Treatments of Cognitive Deficits

Thérapie 65 (5) 415-522 - doi : 10.2515/therapie/2010058
L'histamine exerce ses effets centraux en activant des récepteurs H1,H2 et H3. Le récepteur H3 inhibe la libération de l'histamine cérébrale. Ainsi, les agonistes inverses H3, en levant ce frein, augmentent l'activité des neurones à histamine. Le système histaminergique est un système majeur de la cognition et les agonistes inverses H3 sont pressentis comme thérapeutique potentielle des déficits cognitifs de la maladie d'Alzheimer (AD). Ils sont d'autant plus attendus que d'autres traitements de la maladie, tels que la tacrine ou la mémantine, augmentent aussi, mais par d'autres mécanismes, la neurotransmission histaminergique. Il existe une perte importante de neurones histaminergiques dans l'AD, mais la mesure des taux du métabolite de l'histamine dans le LCR de patients atteints d'AD montre que leur activité globale n'est diminuée que de 25 %. Ces données montrent qu'il devrait bien être possible d'activer les neurones histaminergiques dans l'AD. 

The central effects of histamine are mediated by H1, H2 and H3 receptors. The H3 receptor inhibits histamine release in brain. Therefore, H3 receptor inverse agonists, by suppressing this brake, enhance histamine neuron activity. The histaminergic system plays a major role in cognition and H3 receptor inverse agonists are expected to be a potential therapeutics for cognitive deficits of Alzheimer’s disease (AD). They are eagerly awaited inasmuch as other treatments of the disease, such as tacrine or memantine, also enhance, through different mechanisms, histaminergic neurotransmission. An important loss of histaminergic neurons has been observed in AD. In contrast, levels of the histamine metabolite in the CSF of AD patients show that their global activity is decreased by only 25%. This indicates that activating histamine neurons in AD can be envisaged.

L’histamine exerce ses effets centraux en activant des récepteurs H1,H2 et H3. Le récepteur H3 inhibe la libération de l’histamine cérébrale. Ainsi, les agonistes inverses H3, en levant ce frein, augmentent l’activité des neurones à histamine. Le système histaminergique est un système majeur de la cognition et les agonistes inverses H3 sont pressentis comme thérapeutique potentielle des déficits cognitifs de la maladie d’Alzheimer (AD). Ils sont d’autant plus attendus que d’autres traitements de la maladie, tels que la tacrine ou la mémantine, augmentent aussi, mais par d’autres mécanismes, la neurotransmission histaminergique. Il existe une perte importante de neurones histaminergiques dans l’AD, mais la mesure des taux du métabolite de l’histamine dans le LCR de patients atteints d’AD montre que leur activité globale n’est diminuée que de 25 %. Ces données montrent qu’il devrait bien être possible d’activer les neurones histaminergiques dans l’AD.

The central effects of histamine are mediated by H1, H2 and H3 receptors. The H3 receptor inhibits histamine release in brain. Therefore, H3 receptor inverse agonists, by suppressing this brake, enhance histamine neuron activity. The histaminergic system plays a major role in cognition and H3 receptor inverse agonists are expected to be a potential therapeutics for cognitive deficits of Alzheimer’s disease (AD). They are eagerly awaited inasmuch as other treatments of the disease, such as tacrine or memantine, also enhance, through different mechanisms, histaminergic neurotransmission. An important loss of histaminergic neurons has been observed in AD. In contrast, levels of the histamine metabolite in the CSF of AD patients show that their global activity is decreased by only 25%. This indicates that activating histamine neurons in AD can be envisaged.

Gbahou F., Davenas E., Morisset S. and Arrang J.M.  (2010)

Effects of betahistine at histamine H3 receptors : mixed inverse agonism/agonism in vitro and partial inverse agonism in vivo

Journal of Pharmacology and Experimental Therapeutics 334 (3) 945-954 - doi : 10.1124/jpet.110.168633
We previously suggested that therapeutic effects of betahistine in vestibular disorders result from its antagonist properties at histamine H(3) receptors (H(3)Rs). However, H(3)Rs exhibit constitutive activity, and most H(3)R antagonists act as inverse agonists. Here, we have investigated the effects of betahistine at recombinant H(3)R isoforms. On inhibition of cAMP formation and [(3)H]arachidonic acid release, betahistine behaved as a nanomolar inverse agonist and a micromolar agonist. Both effects were suppressed by pertussis toxin, were found at all isoforms tested, and were not detected in mock cells, confirming interactions at H(3)Rs. The inverse agonist potency of betahistine and its affinity on [(125)I]iodoproxyfan binding were similar in rat and human. We then investigated the effects of betahistine on histamine neuron activity by measuring tele-methylhistamine (t-MeHA) levels in the brains of mice. Its acute intraperitoneal administration increased t-MeHA levels with an ED(50) of 0.4 mg/kg, indicating inverse agonism. At higher doses, t-MeHA levels gradually returned to basal levels, a profile probably resulting from agonism. After acute oral administration, betahistine increased t-MeHA levels with an ED(50) of 2 mg/kg, a rightward shift probably caused by almost complete first-pass metabolism. In each case, the maximal effect of betahistine was lower than that of ciproxifan, indicating partial inverse agonism. After an oral 8-day treatment, the only effective dose of betahistine was 30 mg/kg, indicating that a tolerance had developed. These data strongly suggest that therapeutic effects of betahistine result from an enhancement of histamine neuron activity induced by inverse agonism at H(3) autoreceptors.

We previously suggested that therapeutic effects of betahistine in vestibular disorders result from its antagonist properties at histamine H(3) receptors (H(3)Rs). However, H(3)Rs exhibit constitutive activity, and most H(3)R antagonists act as inverse agonists. Here, we have investigated the effects of betahistine at recombinant H(3)R isoforms. On inhibition of cAMP formation and [(3)H]arachidonic acid release, betahistine behaved as a nanomolar inverse agonist and a micromolar agonist. Both effects were suppressed by pertussis toxin, were found at all isoforms tested, and were not detected in mock cells, confirming interactions at H(3)Rs. The inverse agonist potency of betahistine and its affinity on [(125)I]iodoproxyfan binding were similar in rat and human. We then investigated the effects of betahistine on histamine neuron activity by measuring tele-methylhistamine (t-MeHA) levels in the brains of mice. Its acute intraperitoneal administration increased t-MeHA levels with an ED(50) of 0.4 mg/kg, indicating inverse agonism. At higher doses, t-MeHA levels gradually returned to basal levels, a profile probably resulting from agonism. After acute oral administration, betahistine increased t-MeHA levels with an ED(50) of 2 mg/kg, a rightward shift probably caused by almost complete first-pass metabolism. In each case, the maximal effect of betahistine was lower than that of ciproxifan, indicating partial inverse agonism. After an oral 8-day treatment, the only effective dose of betahistine was 30 mg/kg, indicating that a tolerance had developed. These data strongly suggest that therapeutic effects of betahistine result from an enhancement of histamine neuron activity induced by inverse agonism at H(3) autoreceptors.


2009   Références trouvées : 2

Beghdadi W, Porcherie A, Schneider BS, Morisset S, Dubayle D, Peronet R, Dy M, Louis J, Arrang JM and Mecheri S.  (2009)

Histamine H(3) receptor-mediated signaling protects mice from cerebral malaria

PLoS One (2009) 4(6):e6004

Pantel J, Legendre M, Nivot S, Morisset S, Vie-Luton MP, le Bouc Y, Epelbaum J and Amselem S.   (2009)

Recessive isolated growth hormone deficiency and mutations in the ghrelin receptor

J Clin Endocrinol Metab (2009) 94(11):4334-4341


2008   Références trouvées : 1

Davenas E, Rouleau A, Morisset S, and Arrang JM.  (2008)

Autoregulation of McA-RH7777 Hepatoma cell proliferation by histamine H3 receptors

J. Pharmacol. Exp. Ther. (2008) 326, 406-413


2007   Références trouvées : 2

Humbert-Claude M, Morisset S, Gbahou F and Arrang JM.  (2007)

Histamine H3 and dopamine D2 receptor-mediated [35S]GTPg[S]binding in rat striatum : evidence for additive effects but lack of interactions

Biochem Pharmacol (2007), 73 (8) : 1172-1181

Arrang J, Morisset S and Gbahou F.  (2007)

Constitutive activity of the histamine H3 receptor

Trends Pharmacol Sci, (2007) ; 71 : 350-357


2006   Références trouvées : 1

Pantel J, Legendre M, Cabrol S, Hilal L, Hajaji Y, Morisset S, Nivot S, Vie-Luton MP, Grouselle D, de Kerdanet M, Kadiri A, Epelbaum J, Le Bouc Y, Amselem S.  (2006)

Loss of constitutive activity of the growth hormone secretagogue receptor in familial short stature

J Clin Invest., (2006), 116 : 760-768


2003   Références trouvées : 4

Schwartz JC, Morisset S, Rouleau A, Ligneau X, Gbahou F, Tardivel-Lacombe J, Stark H, Schunack W, Ganellin CR and Arrang JM.  (2003)

Therapeutic implications of constitutive activity of receptors : the example of the histamine H3 receptor

J Neural Transm (2003) Suppl:1-16

Ilien B., Franchet C., Bernard P., Morisset S., Weill C. Bourguignon J., Hibert M. and Galzi J.L.  (2003)

Fluorescence resonance energy transfer to probe human muscarinic M1 receptor structure and drug binding properties

J. Neurochem. (2003) 85:768-778

Gbahou F, Rouleau A, Morisset S, Parmentier R, Crochet S, Lin JS, Ligneau X, Tardivel-Lacombe J, Stark H, Schunack W, Ganellin CR, Schwartz JC and Arrang JM.  (2003)

Protean agonism at histamine H3 receptors in vitro and in vivo

Proc Natl Acad Sci U S A (2003) 100:11086-11091

Arrang J.M., Morisset S., Rouleau A., Gbahou F., Ligneau X., Tardivel-Lacombe J.,. Stark H., Schunack W., Ganellin C.R., Schwartz J.C.  (2003)

Constitutive activity of the recombinant and native histamine H3 receptor.

Dans ‘’Inverse Agonism’’ - Esteve Foundation Symposia. Vol.10. Edité par A. P. Ijzerman. Elsevier, Amsterdam, (2003), 139-151


2002   Références trouvées : 3

Rouleau A., Ligneau X., Tardivel-Lacombe J., Morisset S., Gbahou F., Schwartz J.C., Arrang J.M.  (2002)

Histamine H3-receptor-mediated [35S]GTP gamma[S] binding : evidence for constitutive activity of the recombinant and native rat and human H3 receptors

Br J Pharmacol. (2002) 135, 383-392

Morisset S., Pilon C., Tardivel-Lacombe J., Weinstein D., Rostene W., Betancur C., Sokoloff P., Schwartz J.C. and Arrang J.M.  (2002)

Acute and chronic effects of methamphetamine on tele-methylhistamine levels in mouse brain : selective involvement of the D(2) and not D(3) receptor

J. Pharmacol. Exp. Ther. (2002) 300, 621-628

Chotard C., Ouimet T., Morisset S., Sahm U., Schwartz J.C. and Tottier S.  (2002)

Effects of histamine H3 receptor agonist and antagonist on histamine co-transmitter expression in rat brain

J. Neural. Transm. (2002) 109, 293-306


2001   Références trouvées : 4

Tardivel-Lacombe J., Morisset S., Gbahou F., Schwartz J.C. and Arrang J.M.   (2001)

Chromosomal mapping and organization of human histamine H3 receptor.

Neuroreport (2001) 12, 321-324

Schwartz J.C., Morisset S., Rouleau A., Tardivel-Lacombe J., Gbahou F., Ligneau X., Heron A., Sasse A., Stark H., Schunack W., Ganellin C.R., and Arrang J.M.  (2001)

Application of genomics to drug design : the example of the histamine H3 receptor

Eur Neuropsychopharmacol. (2001) 11, 441-448

Morisset S., Sasse A., Gbahou F., Héron A., Ligneau X., Tardivel-Lacombe J., Schwartz J.C. and Arrang J.M.  (2001)

The rat H3 receptor : gene organization and multiple isoforms

Biochem. Biophys. Res. Commun. (2001) 280, 75-80

Arrang JM., Morisset S., Rouleau A., Tardivel-Lacombe J. Gbahou F., Ligneau X., Héron A., Sasse A., Stark H., Schunack W., Ganellin C.R. and Schwartz J.C.  (2001)

The histamine H3 receptor : gene organization, multiple isoforms, constitutive activity and molecular pharmacology

Dans ‘’Histamine Research in the New Millenium’’. Edité par T. Watanabe, H. Timmermann et K. Yanai. Elsevier, Amsterdam, (2001), 9-21


2000   Références trouvées : 5

Tardivel-Lacombe J., Rouleau A., Héron A., Morisset S., Pillot C., Cauchois V., Schwartz J.C. and Arrang J.M.  (2000)

Cloning and cerebral expression of the guinea pig histamine H3 receptor : evidence for two isoforms

NeuroReport (2000) 11 (4) 521-524

Morisset S., Traiffort E., Arrang J.M. and Schwartz J.C.  (2000)

Changes in histamine H3-receptor responsiveness in mouse brain

J. Neurochem. (2000) 74, 339-346

Ligneau X., Morisset S., Tardivel-Lacombe J., Gbahou F., Ganellin C.R., Stark H., Schunack W., Schwartz J.C.and Arrang J.M.  (2000)

Distinct pharmacology of the rat and human histamine H3 receptors : roles of the two amino acids in the third transmembrane domain

Br. J. Pharmacol. (2000) 131, 1247-1250

Ito C., Morisset S., Krebs M.O., Olié J., Loô H., Poirier M.F., Lannfelt L., Schwartz J.C. and Arrang J.M.  (2000)

Histamine H2 receptor gene variants : lack of association with schizophrenia

Mol. Psychiatry. (2000) 5 159-164

Morisset S., Rouleau A., Ligneau X., Gbahou F., Tardivel-Lacombe J., Stark H., Schunack W., Ganellin C.R., Schwartz J.C. and Arrang J.M.  (2000)

High constitutive activity of the native H3 receptor regulates histamine neurons in brain

Nature (2000), 408, 860-864


1999   Références trouvées : 2

Morisset S., Sahm U.G., Traiffort E., Tardivel-Lacombe J., Arrang J.M., and Schwartz J.C.  (1999)

Atypical neuroleptics enhance histamine turnover in brain via 5HT2A receptor blockade

J. Pharmacol. Exp. Ther. (1999) 268 : 590-596

Arrang J.M., Morisset S., Ito C., Tardivel-Lacombe J., Krebs M.O., Olié J., Loô H., Poirier M.F., Jönsson E., Sedvall G., Crocq M.A., Sokoloff J.C. and Schwartz J.C.  (1999)

Potential role of histamine in schizophrenia

Eur. Neuropsychopharmacol. (1999) 9, S.174


1998   Références trouvées : 1

Arrang J.M., Morisset S., Pillot C. and Schwartz J.C.  (1998)

Subclassification of histamine receptors, H3-receptor subtypes ? Localization of H3 receptors in the brain, in The Histamine H3 Receptor, a Target for New Drugs

Leurs R. and Timmermam H., eds, Elsevier, Amsterdam, (1998) 1-12


1996   Références trouvées : 1

Morisset S., Traiffort E., and Schwartz J.C.  (1996)

Inhibition of histamine versus acetylcholine metabolism as a mechanism of tacrine activity

Eur. J. Pharmacol. (1996) 315 : 1-2


Mots-clés

Chargé de recherche , Signalisation cellulaire