scholarly journals GluN2A and GluN2B NMDA receptors use distinct allosteric routes

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Meilin Tian ◽  
David Stroebel ◽  
Laura Piot ◽  
Mélissa David ◽  
Shixin Ye ◽  
...  
Keyword(s):  
Nmda Receptors ◽  
Molecular Mechanisms ◽  
Adult Brain ◽  
Long Distance ◽  
Biological Regulation ◽  
Allosteric Control ◽  
Synapse Maturation ◽  
Multiple Levels ◽  
Allosteric Mechanisms ◽  
And Behavior

AbstractAllostery represents a fundamental mechanism of biological regulation that involves long-range communication between distant protein sites. It also provides a powerful framework for novel therapeutics. NMDA receptors (NMDARs), glutamate-gated ionotropic receptors that play central roles in synapse maturation and plasticity, are prototypical allosteric machines harboring large extracellular N-terminal domains (NTDs) that provide allosteric control of key receptor properties with impact on cognition and behavior. It is commonly thought that GluN2A and GluN2B receptors, the two predominant NMDAR subtypes in the adult brain, share similar allosteric transitions. Here, combining functional and structural interrogation, we reveal that GluN2A and GluN2B receptors utilize different long-distance allosteric mechanisms involving distinct subunit-subunit interfaces and molecular rearrangements. NMDARs have thus evolved multiple levels of subunit-specific allosteric control over their transmembrane ion channel pore. Our results uncover an unsuspected diversity in NMDAR molecular mechanisms with important implications for receptor physiology and precision drug development.

scholarly journals The Toll Route to Structural Brain Plasticity

2021 ◽  
Vol 12 ◽  
Author(s):  
Guiyi Li ◽  
Alicia Hidalgo
Keyword(s):  
Human Brain ◽  
Molecular Mechanisms ◽  
Brain Plasticity ◽  
Model Organism ◽  
Structural Plasticity ◽  
Fruit Fly ◽  
Adult Brain ◽  
And Behavior ◽  
Structural Brain

The human brain can change throughout life as we learn, adapt and age. A balance between structural brain plasticity and homeostasis characterizes the healthy brain, and the breakdown of this balance accompanies brain tumors, psychiatric disorders, and neurodegenerative diseases. However, the link between circuit modifications, brain function, and behavior remains unclear. Importantly, the underlying molecular mechanisms are starting to be uncovered. The fruit-fly Drosophila is a very powerful model organism to discover molecular mechanisms and test them in vivo. There is abundant evidence that the Drosophila brain is plastic, and here we travel from the pioneering discoveries to recent findings and progress on molecular mechanisms. We pause on the recent discovery that, in the Drosophila central nervous system, Toll receptors—which bind neurotrophin ligands—regulate structural plasticity during development and in the adult brain. Through their topographic distribution across distinct brain modules and their ability to switch between alternative signaling outcomes, Tolls can enable the brain to translate experience into structural change. Intriguing similarities between Toll and mammalian Toll-like receptor function could reveal a further involvement in structural plasticity, degeneration, and disease in the human brain.

scholarly journals Gene regulatory networks controlling differentiation, survival, and diversification of hypothalamic Lhx6-expressing GABAergic neurons

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Dong Won Kim ◽  
Kai Liu ◽  
Zoe Qianyi Wang ◽  
Yi Stephanie Zhang ◽  
Abhijith Bathini ◽  
...  
Keyword(s):  
Cortical Neurons ◽  
Regulatory Networks ◽  
Molecular Mechanisms ◽  
Gabaergic Neurons ◽  
Zona Incerta ◽  
Long Distance ◽  
Hypothalamic Neurons ◽  
Cortical Interneuron ◽  
Tangential Migration ◽  
Innate Behaviors

AbstractGABAergic neurons of the hypothalamus regulate many innate behaviors, but little is known about the mechanisms that control their development. We previously identified hypothalamic neurons that express the LIM homeodomain transcription factor Lhx6, a master regulator of cortical interneuron development, as sleep-promoting. In contrast to telencephalic interneurons, hypothalamic Lhx6 neurons do not undergo long-distance tangential migration and do not express cortical interneuronal markers such as Pvalb. Here, we show that Lhx6 is necessary for the survival of hypothalamic neurons. Dlx1/2, Nkx2-2, and Nkx2-1 are each required for specification of spatially distinct subsets of hypothalamic Lhx6 neurons, and that Nkx2-2+/Lhx6+ neurons of the zona incerta are responsive to sleep pressure. We further identify multiple neuropeptides that are enriched in spatially segregated subsets of hypothalamic Lhx6 neurons, and that are distinct from those seen in cortical neurons. These findings identify common and divergent molecular mechanisms by which Lhx6 controls the development of GABAergic neurons in the hypothalamus.

scholarly journals Targeting bone morphogenetic protein signalling in midbrain dopaminergic neurons as a therapeutic approach in Parkinson's disease

2017 ◽  
Vol 1 (2) ◽  
Author(s):  
Gerard W. O'Keeffe ◽  
Shane V. Hegarty ◽  
Aideen M. Sullivan
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neurotrophic Factors ◽  
Neurotrophic Factor ◽  
Molecular Mechanisms ◽  
Axon Growth ◽  
Nervous System Development ◽  
Adult Brain ◽  
Bmp Receptors

Parkinson's disease (PD) is the second most common neurodegenerative disease, characterized by the degeneration of midbrain dopaminergic (mDA) neurons and their axons, and aggregation of α-synuclein, which leads to motor and late-stage cognitive impairments. As the motor symptoms of PD are caused by the degeneration of a specific population of mDA neurons, PD lends itself to neurotrophic factor therapy. The goal of this therapy is to apply a neurotrophic factor that can slow down, halt or even reverse the progressive degeneration of mDA neurons. While the best known neurotrophic factors are members of the glial cell line-derived neurotrophic factor (GDNF) family, their lack of clinical efficacy to date means that it is important to continue to study other neurotrophic factors. Bone morphogenetic proteins (BMPs) are naturally secreted proteins that play critical roles during nervous system development and in the adult brain. In this review, we provide an overview of the BMP ligands, BMP receptors (BMPRs) and their intracellular signalling effectors, the Smad proteins. We review the available evidence that BMP–Smad signalling pathways play an endogenous role in mDA neuronal survival in vivo, before outlining how exogenous application of BMPs exerts potent effects on mDA neuron survival and axon growth in vitro and in vivo. We discuss the molecular mechanisms that mediate these effects, before highlighting the potential of targeting the downstream effectors of BMP–Smad signalling as a novel neuroprotective approach to slow or stop the degeneration of mDA neurons in PD.

scholarly journals Systematic functional characterization of antisense eRNA of protocadherin α composite enhancer

2021 ◽  
Vol 35 (19-20) ◽  
pp. 1383-1394
Author(s):  
Yuxiao Zhou ◽  
Siyuan Xu ◽  
Mo Zhang ◽  
Qiang Wu
Keyword(s):  
Gene Expression ◽  
Molecular Mechanisms ◽  
Single Cells ◽  
Functional Characterization ◽  
Three Dimensional ◽  
Elongation Factor ◽  
Locked Nucleic Acid ◽  
Loop Formation ◽  
Long Distance ◽  
Enhancer Region

Enhancers generate bidirectional noncoding enhancer RNAs (eRNAs) that may regulate gene expression. At present, the eRNA function remains enigmatic. Here, we report a 5′ capped antisense eRNA PEARL (Pcdh eRNA associated with R-loop formation) that is transcribed from the protocadherin (Pcdh) α HS5-1 enhancer region. Through loss- and gain-of-function experiments with CRISPR/Cas9 DNA fragment editing, CRISPRi, and CRISPRa, as well as locked nucleic acid strategies, in conjunction with ChIRP, MeDIP, DRIP, QHR-4C, and HiChIP experiments, we found that PEARL regulates Pcdhα gene expression by forming local RNA–DNA duplexes (R-loops) in situ within the HS5-1 enhancer region to promote long-distance chromatin interactions between distal enhancers and target promoters. In particular, increased levels of eRNA PEARL via perturbing transcription elongation factor SPT6 lead to strengthened local three-dimensional chromatin organization within the Pcdh superTAD. These findings have important implications regarding molecular mechanisms by which the HS5-1 enhancer regulates stochastic Pcdhα promoter choice in single cells in the brain.

scholarly journals Proteomic analysis of anti-angiogenic effects by conbercept in the mice with oxygen induced retinopathy

2020 ◽  
Vol 13 (12) ◽  
pp. 1844-1853
Author(s):  
Ji Jin ◽  
Gao-Qin Liu ◽  
Pei-Rong Lu
Keyword(s):  
Risk Factors ◽  
Molecular Mechanisms ◽  
Hypoxia Inducible Factor ◽  
Fibrin Clot ◽  
Biological Regulation ◽  
Cellular Processes ◽  
Novel Proteins ◽  
Oxygen Induced Retinopathy ◽  
Single Organism ◽  
Group 2

AIM: To analyze the retinal proteomes with and without conbercept treatments in mice with oxygen-induced retinopathy (OIR) and identify proteins involved in the molecular mechanisms mediated by conbercept. METHODS: OIR was induced in fifty-six C57BL/6J mouse pups and randomly divided into four groups. Group 1: Normal17 (n=7), mice without OIR and treated with normal air. Group 2: OIR12/EXP1 (n=14), mice received 75% oxygen from postnatal day (P) 7 to 12. Group 3: OIR17/Control (n=14), mice received 75% oxygen from P7 to P12 and then normal air to P17. Group 4: Lang17/EXP2 (n=21), mice received 75% oxygen from P7 to P12 with intravitreal injection of 1 µL conbercept at the concentration of 10 mg/mL at P12, and then normal air from P12 to P17. Liquid Chromatography-Mass Spectrometry (LC-MS)/MS data were reviewed to find proteins that were up-regulated after the conbercept treatment. Gene ontology (GO) analysis was performed of conbercept-mediated changes in proteins involved in single-organism processes, biological regulation, cellular processes, immune responses, metabolic processes, locomotion and multiple-organism processes. RESULTS: Conbercept induced a reversal of hypoxia-inducible factor 1 signaling pathway as revealed by the Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis and also induced down-regulation of proteins involved in blood coagulation and fibrin clot formation as demonstrated by the Database for Annotation, Visualization and Integrated Discovery (DAVID) and the stimulation of interferon genes studies. These appear to be risk factors of retinal fibrosis. Additional conbercept-specific fibrosis risk factors were also identified and may serve as therapeutic targets for fibrosis. CONCLUSION: Our studies reveal that many novel proteins are differentially regulated by conbercept. The new insights may warrant a valuable resource for conbercept treatment.

scholarly journals Towards comprehensive allosteric control over protein activity

2018 ◽  
Author(s):  
Enrico Guarnera ◽  
Igor N. Berezovsky
Keyword(s):  
Ligand Binding ◽  
Molecular Mechanisms ◽  
Allosteric Regulation ◽  
Mode Switching ◽  
Contact Network ◽  
Protein Activity ◽  
Theoretical Understanding ◽  
Functional Sites ◽  
Allosteric Control ◽  
Allosteric Communication

AbstractOn the basis of the perturbation nature of allosteric communication, a computational framework is proposed for estimating the energetics of signaling caused by the ligand binding and mutations. The perturbations are modelled as alterations of the strenght of interactions in the protein contact network in the binding sites and neighborhoods of mutated residues. The combination of protein harmonic modelling with effect of perturbations and the estimate of local partition functions allow one to evaluate the energetics of allosteric communication at single residue level. The potential allosteric effect of a protein residue position, modulation range, is given by the difference between responses to stabilizing and destabilizing mutations. We show a versatility of the approach on three case studies of proteins with different mechanisms of allosteric regulation, testing it on their known regulatory and functional sites. Allosteric Signaling Maps (ASMs) obtained on the basis of residue-by-residue scanning are proposed as a comprehensive tool to explore a relationship between mutations allosterically modulating protein activity and those that mainly affect protein stability. Analysis of ASMs shows distance dependence of the mode switching in allosteric signaling, emphasizing the role of domains/subunits in protein allosteric communication as elements of a percolative system. Finally, ASMs can be used to complement and tune already existing signaling and to design new elements of allosteric regulation.SignificanceUniversality of allosteric signaling in proteins, molecular machines, and receptors and great advantages of prospected allosteric drugs in highly specific, non-competitive, and modulatory nature of their actions call for deeper theoretical understanding of allosteric communication. In the energy landscape paradigm underliying the molecular mechanisms of protein function, allosteric signalling is the result of any perturbation, such as ligand binding, mutations, intermolecular interactions etc. We present a computational model, allowing to tackle the problem of modulating the energetics of protein allosteric communication. Using this method, Allosteric Signaling Maps (ASMs) are proposed as an approach to exhaustively describe allosteric signaling in the protein, making it possible to take protein activity under allosteric control.

Medicine

Mind-Society ◽  
2019 ◽  
pp. 259-291
Author(s):  
Paul Thagard
Keyword(s):  
Mental Illness ◽  
Molecular Mechanisms ◽  
Social Cognitive ◽  
Neural Mechanisms ◽  
Mental Illnesses ◽  
New Approach ◽  
Treatment Of Depression ◽  
Repair Mechanisms ◽  
Multiple Levels ◽  
Simple Reduction

All mental illnesses involve breakdowns in neural mechanisms for emotions that do not simply reduce to isolated mental, social, or chemical causes. The case of depression shows how illness results from the interaction of many causes that can be social, cognitive, neural, and molecular. Depression emerges from the interactions of mechanisms at all of these levels in a way that exemplifies emergence rather than simple reduction. Accordingly, treatment of depression often benefits from trying to repair mechanisms at multiple levels, most commonly by employing psychotherapy to make changes in mental representations and by employing antidepressants to change neurochemistry. Social cognitivism, the approach that integrates social, mental, neural, and molecular mechanisms, provides a new approach to explaining mental illness thanks to semantic pointer theories of cognition and communication.

Stress and Bipolar Disorder

2020 ◽  
pp. 297-328
Author(s):  
Richard McCarty
Keyword(s):  
Bipolar Disorder ◽  
Animal Models ◽  
Molecular Mechanisms ◽  
Clock Genes ◽  
Mood State ◽  
Mouse Strains ◽  
Transporter Protein ◽  
Circadian Clock Genes ◽  
Dopamine Signaling ◽  
And Behavior

Animal models of bipolar disorder (BD) should capture the switching of mood states from mania to depression and vice versa. Dopamine signaling pathways in brain, including variations in the dopamine transporter protein, have been a focus of many animal models of BD. Another aspect of BD in humans is reflected in circadian and seasonal changes in onset of symptoms. Other animal models of BD include the Myshkin and Madison mouse strains, both of which display mania-like behavior that is reversed by treatment with lithium or valproic acid. Another experimental approach has been to manipulate circadian clock genes and examine effects on dopamine signaling and behavior. Finally, manipulations of risk genes for BD in laboratory mice have advanced our understanding of the molecular mechanisms involved in extreme alterations in mood state.

scholarly journals circStrn3 is involved in bone cancer pain regulation in a rat model

2020 ◽  
Vol 52 (5) ◽  
pp. 495-505
Author(s):  
Yiwen Zhang ◽  
Xiaoxia Zhang ◽  
Zumin Xing ◽  
Shuyi Tang ◽  
Hanwen Chen ◽  
...  
Keyword(s):  
Cancer Pain ◽  
Rat Model ◽  
Molecular Mechanisms ◽  
Bone Cancer ◽  
Test Body ◽  
Differentially Expressed ◽  
Bone Cancer Pain ◽  
Biological Regulation ◽  
Cellular Processes ◽  
Simplex Infection

Abstract Bone cancer pain (BCP) is a common chronic pain that is caused by a primary or metastatic bone tumor. More detailed molecular mechanisms of BCP are warranted. In this study, we established a BCP rat model. The von Frey hair test, body weight, and hematoxylin and eosin staining were employed. We screened differentially expressed circRNAs (DECs) between the BCP group and sham group. The results revealed that 850 DECs were significantly up-regulated and 644 DECs were significantly down-regulated in the BCP group. Furthermore, we identified 1177 differentially expressed genes (DEGs) significantly up-regulated and 565 DEGs significantly down-regulated in the BCP group. Gene Ontology annotation of all 1742 DEGs revealed that biological regulation of metabolic processes, cellular processes, and binding were the top enriched terms. For Kyoto Encyclopedia of Genes and Genomes analysis, phagosome, HTLV-I infection, proteoglycans in cancer, and herpes simplex infection were significantly enriched in this study. In addition, we identified four selected circRNAs, chr6:72418120|72430205, chr20:7561057|7573740, chr18:69943105|69944476, and chr5:167516581|167558250, by quantitative real time PCR. chr6:72418120|72430205 (circStrn3) was selected for further study based on expression level and the circRNA–miRNA–mRNA network table. Western blot analysis suggested that knockdown of circStrn3 could effectively induce Walker 256 cell apoptosis. In summary, our study provided a more in-depth understanding of the molecular mechanisms of BCP.

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