The Experts below are selected from a list of 31812 Experts worldwide ranked by ideXlab platform
Horst Vogel - One of the best experts on this subject based on the ideXlab platform.
-
asymmetric opening of the homopentameric 5 ht3a Serotonin Receptor in lipid bilayers
Nature Communications, 2021Co-Authors: Yingyi Zhang, Pratricia M Dijkman, Rongfeng Zou, Martina Zandllang, Ricardo Sanchez, Luise Eckhardtstrelau, Harald Kofeler, Horst VogelAbstract:Pentameric ligand-gated ion channels (pLGICs) of the Cys-loop Receptor family are key players in fast signal transduction throughout the nervous system. They have been shown to be modulated by the lipid environment, however the underlying mechanism is not well understood. We report three structures of the Cys-loop 5-HT3A Serotonin Receptor (5HT3R) reconstituted into saposin-based lipid bilayer discs: a symmetric and an asymmetric apo state, and an asymmetric agonist-bound state. In comparison to previously published 5HT3R conformations in detergent, the lipid bilayer stabilises the Receptor in a more tightly packed, 'coupled' state, involving a cluster of highly conserved residues. In consequence, the agonist-bound Receptor conformation adopts a wide-open pore capable of conducting sodium ions in unbiased molecular dynamics (MD) simulations. Taken together, we provide a structural basis for the modulation of 5HT3R by the membrane environment, and a model for asymmetric activation of the Receptor.
-
asymmetric opening of the homopentameric 5 ht 3a Serotonin Receptor in lipid bilayers
Nature Communications, 2021Co-Authors: Yingyi Zhang, Pratricia M Dijkman, Rongfeng Zou, Martina Zandllang, Ricardo Sanchez, Luise Eckhardtstrelau, Harald Kofeler, Horst VogelAbstract:Pentameric ligand-gated ion channels (pLGICs) of the Cys-loop Receptor family are key players in fast signal transduction throughout the nervous system. They have been shown to be modulated by the lipid environment, however the underlying mechanism is not well understood. We report three structures of the Cys-loop 5-HT3A Serotonin Receptor (5HT3R) reconstituted into saposin-based lipid bilayer discs: a symmetric and an asymmetric apo state, and an asymmetric agonist-bound state. In comparison to previously published 5HT3R conformations in detergent, the lipid bilayer stabilises the Receptor in a more tightly packed, 'coupled' state, involving a cluster of highly conserved residues. In consequence, the agonist-bound Receptor conformation adopts a wide-open pore capable of conducting sodium ions in unbiased molecular dynamics (MD) simulations. Taken together, we provide a structural basis for the modulation of 5HT3R by the membrane environment, and a model for asymmetric activation of the Receptor.
Marcus Niebert - One of the best experts on this subject based on the ideXlab platform.
-
Persistent Expression of Serotonin Receptor 5b Alters Breathing Behavior in Male MeCP2 Knockout Mice
Frontiers in molecular neuroscience, 2018Co-Authors: Steffen Vogelgesang, Marcus Niebert, Anne M. Bischoff, Swen Hülsmann, Till ManzkeAbstract:Mutations in the transcription factor methyl-CpG-binding protein 2 (MeCP2) cause a delayed neurodevelopmental disorder known as Rett syndrome (RTT). Among many other neurological problems RTT patients show irregular breathing with recurrent apneas or breath-holdings. Mecp2–deficient mice, which recapitulate this breathing phenotype, show a dysregulated expression of G-protein-coupled Serotonin Receptor 5-ht5b (Htr5b) in the brainstem. Since 5-ht5b Receptors couple to Gi proteins, we measured cAMP levels in brainstem tissue, and found that, unlike in WT and Mecp2-/y;Htr5b-/- mice, cAMP levels in Mecp2-/y mice were decreased. Using unrestrained whole-body plethysmography, we investigated, whether the persistence of 5-ht5b expression in older Mecp2-/y mice is contributing to the respiratory phenotype. The breathing of MeCP2-deficient male mice at postnatal day 40 was characterized by a slow breathing rate and the occurrence of prolonged respiratory pauses. In contrast, we found that both breathing rate and number of pauses in MeCP2-deficient mice, which also lacked the 5-ht5b Receptor (Mecp2-/y;Htr5b-/-) was indistinguishable from wild type (WT) and Htr5b-/- mice. Taken together, our data points towards a role of 5-ht5b Receptors within the breathing complex phenotype of MeCP2-deficient mice.
-
the Serotonin Receptor subtype 5b specifically interacts with Serotonin Receptor subtype 1a
Frontiers in Molecular Neuroscience, 2017Co-Authors: Sabine Niebert, Steffen Vogelgesang, Till Manzke, Gijsbert J Van Belle, Marcus NiebertAbstract:Previously, we described the dysregulation of Serotonin Receptor subtype 5b (5-ht5b) in a mouse model of Rett syndrome (RTT). 5-ht5b has not been extensively studied, so we set out to characterize it in more detail. Unlike common cell surface Receptors, 5-ht5b displays no membrane expression, while Receptor clusters are located in endosomes. This unusual subcellular localization is at least in part controlled by glycosylation of the N-terminus, with 5-ht5b possessing fewer glycosylation sites than related Receptors. We analyzed whether the localization to endosomes has any functional relevance and found that 5-ht5b Receptors can specifically interact with 5-HT1A Receptors and retain them in endosomal compartments. This interaction reduces 5-HT1A surface expression and is mediated by interactions between the fourth and fifth trans-membrane domain. This possibly presents a mechanism by which 5-ht5b Receptors regulate the activity the other Serotonin Receptor.
-
Serotonin Receptor 1a modulated phosphorylation of glycine Receptor α3 controls breathing in mice
Journal of Clinical Investigation, 2010Co-Authors: Till Manzke, Steffen Vogelgesang, Marcus Niebert, Swen Hülsmann, Uwe R Koch, Alex Caley, Evgeni Ponimaskin, Ulrike Muller, Trevor G Smart, Robert J HarveyAbstract:Rhythmic breathing movements originate from a dispersed neuronal network in the medulla and pons. Here, we demonstrate that rhythmic activity of this respiratory network is affected by the phosphorylation status of the inhibitory glycine Receptor alpha 3 subtype (GlyR alpha 3), which controls glutamatergic and glycinergic neuronal discharges, subject to serotonergic modulation. Serotonin Receptor type 1A-specific (5-HTR1A-specific) modulation directly induced dephosphorylation of GlyR alpha 3 Receptors, which augmented inhibitory glycine-activated chloride currents in HEK293 cells coexpressing 5-HTR1A and GlyR alpha 3. The 5-HTR1A-GlyR alpha 3 signaling pathway was distinct from opioid Receptor signaling and efficiently counteracted opioid-induced depression of breathing and consequential apnea in mice. Paradoxically, this rescue of breathing originated from enhanced glycinergic synaptic inhibition of glutamatergic and glycinergic neurons and caused disinhibition of their target neurons. Together, these effects changed respiratory phase alternations and ensured rhythmic breathing in vivo. GlyR alpha 3-deficient mice had an irregular respiratory rhythm under baseline conditions, and systemic 5-HTR1A activation failed to remedy opioid-induced respiratory depression in these mice. Delineation of this 5-HTR1A-GlyR alpha 3 signaling pathway offers a mechanistic basis for pharmacological treatment of opioid-induced apnea and other breathing disturbances caused by disorders of inhibitory synaptic transmission, such as hyperekplexia, hypoxia/ischemia, and brainstem infarction.
-
Serotonin Receptor 1a modulated phosphorylation of glycine Receptor α3 controls breathing in mice
Journal of Clinical Investigation, 2010Co-Authors: Till Manzke, Steffen Vogelgesang, Marcus Niebert, Swen Hülsmann, Uwe R Koch, Alex Caley, Evgeni Ponimaskin, Ulrike Muller, Trevor G Smart, Robert J HarveyAbstract:Rhythmic breathing movements originate from a dispersed neuronal network in the medulla and pons. Here, we demonstrate that rhythmic activity of this respiratory network is affected by the phosphorylation status of the inhibitory glycine Receptor alpha 3 subtype (GlyR alpha 3), which controls glutamatergic and glycinergic neuronal discharges, subject to serotonergic modulation. Serotonin Receptor type 1A-specific (5-HTR1A-specific) modulation directly induced dephosphorylation of GlyR alpha 3 Receptors, which augmented inhibitory glycine-activated chloride currents in HEK293 cells coexpressing 5-HTR1A and GlyR alpha 3. The 5-HTR1A-GlyR alpha 3 signaling pathway was distinct from opioid Receptor signaling and efficiently counteracted opioid-induced depression of breathing and consequential apnea in mice. Paradoxically, this rescue of breathing originated from enhanced glycinergic synaptic inhibition of glutamatergic and glycinergic neurons and caused disinhibition of their target neurons. Together, these effects changed respiratory phase alternations and ensured rhythmic breathing in vivo. GlyR alpha 3-deficient mice had an irregular respiratory rhythm under baseline conditions, and systemic 5-HTR1A activation failed to remedy opioid-induced respiratory depression in these mice. Delineation of this 5-HTR1A-GlyR alpha 3 signaling pathway offers a mechanistic basis for pharmacological treatment of opioid-induced apnea and other breathing disturbances caused by disorders of inhibitory synaptic transmission, such as hyperekplexia, hypoxia/ischemia, and brainstem infarction.
Till Manzke - One of the best experts on this subject based on the ideXlab platform.
-
Persistent Expression of Serotonin Receptor 5b Alters Breathing Behavior in Male MeCP2 Knockout Mice
Frontiers in molecular neuroscience, 2018Co-Authors: Steffen Vogelgesang, Marcus Niebert, Anne M. Bischoff, Swen Hülsmann, Till ManzkeAbstract:Mutations in the transcription factor methyl-CpG-binding protein 2 (MeCP2) cause a delayed neurodevelopmental disorder known as Rett syndrome (RTT). Among many other neurological problems RTT patients show irregular breathing with recurrent apneas or breath-holdings. Mecp2–deficient mice, which recapitulate this breathing phenotype, show a dysregulated expression of G-protein-coupled Serotonin Receptor 5-ht5b (Htr5b) in the brainstem. Since 5-ht5b Receptors couple to Gi proteins, we measured cAMP levels in brainstem tissue, and found that, unlike in WT and Mecp2-/y;Htr5b-/- mice, cAMP levels in Mecp2-/y mice were decreased. Using unrestrained whole-body plethysmography, we investigated, whether the persistence of 5-ht5b expression in older Mecp2-/y mice is contributing to the respiratory phenotype. The breathing of MeCP2-deficient male mice at postnatal day 40 was characterized by a slow breathing rate and the occurrence of prolonged respiratory pauses. In contrast, we found that both breathing rate and number of pauses in MeCP2-deficient mice, which also lacked the 5-ht5b Receptor (Mecp2-/y;Htr5b-/-) was indistinguishable from wild type (WT) and Htr5b-/- mice. Taken together, our data points towards a role of 5-ht5b Receptors within the breathing complex phenotype of MeCP2-deficient mice.
-
the Serotonin Receptor subtype 5b specifically interacts with Serotonin Receptor subtype 1a
Frontiers in Molecular Neuroscience, 2017Co-Authors: Sabine Niebert, Steffen Vogelgesang, Till Manzke, Gijsbert J Van Belle, Marcus NiebertAbstract:Previously, we described the dysregulation of Serotonin Receptor subtype 5b (5-ht5b) in a mouse model of Rett syndrome (RTT). 5-ht5b has not been extensively studied, so we set out to characterize it in more detail. Unlike common cell surface Receptors, 5-ht5b displays no membrane expression, while Receptor clusters are located in endosomes. This unusual subcellular localization is at least in part controlled by glycosylation of the N-terminus, with 5-ht5b possessing fewer glycosylation sites than related Receptors. We analyzed whether the localization to endosomes has any functional relevance and found that 5-ht5b Receptors can specifically interact with 5-HT1A Receptors and retain them in endosomal compartments. This interaction reduces 5-HT1A surface expression and is mediated by interactions between the fourth and fifth trans-membrane domain. This possibly presents a mechanism by which 5-ht5b Receptors regulate the activity the other Serotonin Receptor.
-
Serotonin Receptor 1a modulated phosphorylation of glycine Receptor α3 controls breathing in mice
Journal of Clinical Investigation, 2010Co-Authors: Till Manzke, Steffen Vogelgesang, Marcus Niebert, Swen Hülsmann, Uwe R Koch, Alex Caley, Evgeni Ponimaskin, Ulrike Muller, Trevor G Smart, Robert J HarveyAbstract:Rhythmic breathing movements originate from a dispersed neuronal network in the medulla and pons. Here, we demonstrate that rhythmic activity of this respiratory network is affected by the phosphorylation status of the inhibitory glycine Receptor alpha 3 subtype (GlyR alpha 3), which controls glutamatergic and glycinergic neuronal discharges, subject to serotonergic modulation. Serotonin Receptor type 1A-specific (5-HTR1A-specific) modulation directly induced dephosphorylation of GlyR alpha 3 Receptors, which augmented inhibitory glycine-activated chloride currents in HEK293 cells coexpressing 5-HTR1A and GlyR alpha 3. The 5-HTR1A-GlyR alpha 3 signaling pathway was distinct from opioid Receptor signaling and efficiently counteracted opioid-induced depression of breathing and consequential apnea in mice. Paradoxically, this rescue of breathing originated from enhanced glycinergic synaptic inhibition of glutamatergic and glycinergic neurons and caused disinhibition of their target neurons. Together, these effects changed respiratory phase alternations and ensured rhythmic breathing in vivo. GlyR alpha 3-deficient mice had an irregular respiratory rhythm under baseline conditions, and systemic 5-HTR1A activation failed to remedy opioid-induced respiratory depression in these mice. Delineation of this 5-HTR1A-GlyR alpha 3 signaling pathway offers a mechanistic basis for pharmacological treatment of opioid-induced apnea and other breathing disturbances caused by disorders of inhibitory synaptic transmission, such as hyperekplexia, hypoxia/ischemia, and brainstem infarction.
-
Serotonin Receptor 1a modulated phosphorylation of glycine Receptor α3 controls breathing in mice
Journal of Clinical Investigation, 2010Co-Authors: Till Manzke, Steffen Vogelgesang, Marcus Niebert, Swen Hülsmann, Uwe R Koch, Alex Caley, Evgeni Ponimaskin, Ulrike Muller, Trevor G Smart, Robert J HarveyAbstract:Rhythmic breathing movements originate from a dispersed neuronal network in the medulla and pons. Here, we demonstrate that rhythmic activity of this respiratory network is affected by the phosphorylation status of the inhibitory glycine Receptor alpha 3 subtype (GlyR alpha 3), which controls glutamatergic and glycinergic neuronal discharges, subject to serotonergic modulation. Serotonin Receptor type 1A-specific (5-HTR1A-specific) modulation directly induced dephosphorylation of GlyR alpha 3 Receptors, which augmented inhibitory glycine-activated chloride currents in HEK293 cells coexpressing 5-HTR1A and GlyR alpha 3. The 5-HTR1A-GlyR alpha 3 signaling pathway was distinct from opioid Receptor signaling and efficiently counteracted opioid-induced depression of breathing and consequential apnea in mice. Paradoxically, this rescue of breathing originated from enhanced glycinergic synaptic inhibition of glutamatergic and glycinergic neurons and caused disinhibition of their target neurons. Together, these effects changed respiratory phase alternations and ensured rhythmic breathing in vivo. GlyR alpha 3-deficient mice had an irregular respiratory rhythm under baseline conditions, and systemic 5-HTR1A activation failed to remedy opioid-induced respiratory depression in these mice. Delineation of this 5-HTR1A-GlyR alpha 3 signaling pathway offers a mechanistic basis for pharmacological treatment of opioid-induced apnea and other breathing disturbances caused by disorders of inhibitory synaptic transmission, such as hyperekplexia, hypoxia/ischemia, and brainstem infarction.
Ricardo Sanchez - One of the best experts on this subject based on the ideXlab platform.
-
asymmetric opening of the homopentameric 5 ht3a Serotonin Receptor in lipid bilayers
Nature Communications, 2021Co-Authors: Yingyi Zhang, Pratricia M Dijkman, Rongfeng Zou, Martina Zandllang, Ricardo Sanchez, Luise Eckhardtstrelau, Harald Kofeler, Horst VogelAbstract:Pentameric ligand-gated ion channels (pLGICs) of the Cys-loop Receptor family are key players in fast signal transduction throughout the nervous system. They have been shown to be modulated by the lipid environment, however the underlying mechanism is not well understood. We report three structures of the Cys-loop 5-HT3A Serotonin Receptor (5HT3R) reconstituted into saposin-based lipid bilayer discs: a symmetric and an asymmetric apo state, and an asymmetric agonist-bound state. In comparison to previously published 5HT3R conformations in detergent, the lipid bilayer stabilises the Receptor in a more tightly packed, 'coupled' state, involving a cluster of highly conserved residues. In consequence, the agonist-bound Receptor conformation adopts a wide-open pore capable of conducting sodium ions in unbiased molecular dynamics (MD) simulations. Taken together, we provide a structural basis for the modulation of 5HT3R by the membrane environment, and a model for asymmetric activation of the Receptor.
-
asymmetric opening of the homopentameric 5 ht 3a Serotonin Receptor in lipid bilayers
Nature Communications, 2021Co-Authors: Yingyi Zhang, Pratricia M Dijkman, Rongfeng Zou, Martina Zandllang, Ricardo Sanchez, Luise Eckhardtstrelau, Harald Kofeler, Horst VogelAbstract:Pentameric ligand-gated ion channels (pLGICs) of the Cys-loop Receptor family are key players in fast signal transduction throughout the nervous system. They have been shown to be modulated by the lipid environment, however the underlying mechanism is not well understood. We report three structures of the Cys-loop 5-HT3A Serotonin Receptor (5HT3R) reconstituted into saposin-based lipid bilayer discs: a symmetric and an asymmetric apo state, and an asymmetric agonist-bound state. In comparison to previously published 5HT3R conformations in detergent, the lipid bilayer stabilises the Receptor in a more tightly packed, 'coupled' state, involving a cluster of highly conserved residues. In consequence, the agonist-bound Receptor conformation adopts a wide-open pore capable of conducting sodium ions in unbiased molecular dynamics (MD) simulations. Taken together, we provide a structural basis for the modulation of 5HT3R by the membrane environment, and a model for asymmetric activation of the Receptor.
Gabriele M Konig - One of the best experts on this subject based on the ideXlab platform.
-
endolides a and b vasopressin and Serotonin Receptor interacting n methylated peptides from the sponge derived fungus stachylidium sp
Organic Letters, 2016Co-Authors: Celso Almeida, Fayrouz El Maddah, Stefan Kehraus, Gregor Schnakenburg, Gabriele M KonigAbstract:The marine-derived fungus Stachylidium sp. was isolated from the sponge Callyspongia sp. cf. C. flammea. Culture on a biomalt medium supplemented with sea salt led to the isolation of two new, most unusual N-methylated peptides, i.e., the tetrapeptides endolide A and B (1 and 2). Both of these contain the very rare amino acid 3-(3-furyl)-alanine. In radioligand binding assays endolide A (1) showed affinity to the vasopressin Receptor 1A with a Ki of 7.04 μM, whereas endolide B (2) exhibited no affinity to the latter Receptor, but was selective toward the Serotonin Receptor 5HT2b with a Ki of 0.77 μM.
