Knowledge about how Toll-like receptors (TLRs) recognize pathogenic ligands is critical to understanding how these receptors are activated and to designing therapeutic compounds that target this family of receptors for inflammatory diseases. The crystal structure of TLR5 in complex with its bacterial ligand flagellin revealed that the ligand-binding mode for TLR5 is distinct from that of previously characterized TLRs. Nevertheless, like other TLRs, TLR5 forms a dimer in response to ligand binding. This work contributes to our current knowledge of TLR function and further demonstrates the ability of TLRs to couple versatile ligand recognition to a conserved receptor signaling mechanism.
{"title":"The structure of the TLR5-flagellin complex: a new mode of pathogen detection, conserved receptor dimerization for signaling.","authors":"Jinghua Lu, Peter D Sun","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Knowledge about how Toll-like receptors (TLRs) recognize pathogenic ligands is critical to understanding how these receptors are activated and to designing therapeutic compounds that target this family of receptors for inflammatory diseases. The crystal structure of TLR5 in complex with its bacterial ligand flagellin revealed that the ligand-binding mode for TLR5 is distinct from that of previously characterized TLRs. Nevertheless, like other TLRs, TLR5 forms a dimer in response to ligand binding. This work contributes to our current knowledge of TLR function and further demonstrates the ability of TLRs to couple versatile ligand recognition to a conserved receptor signaling mechanism.</p>","PeriodicalId":49560,"journal":{"name":"Science Signaling","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2012-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3727914/pdf/nihms-492373.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"30708100","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The skin is the largest sensory organ of the body. It is innervated by a diverse array of primary sensory neurons, including a heterogeneous subset of unmyelinated afferents called C fibers. C fibers, sometimes classified as nociceptors, can detect various painful stimuli, including temperature extremes. However, it is increasingly evident that these afferents respond to various pruritic stimuli and transmit information to the brain that is perceived as itch; this can subsequently drive scratching behavior. Although itch and pain are distinct sensations, they are closely related and can, under certain circumstances, antagonize each other. However, it is not clear precisely when, where, and how the processes generating these two sensations originate and how they are dissociated. Clues have come from the analysis of the activities of specific ligands and their receptors. New data indicate that specific pruritic ligands carrying both itch and pain information are selectively recognized by different G protein–coupled receptors (GPCRs), and this information may be transduced through different intracellular circuits in the same neuron. These findings raise questions about the intracellular mechanisms that preprocess and perhaps encode GPCR-mediated signals.
{"title":"Intracellular signaling and the origins of the sensations of itch and pain.","authors":"Sang-Kyou Han, Melvin I Simon","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>The skin is the largest sensory organ of the body. It is innervated by a diverse array of primary sensory neurons, including a heterogeneous subset of unmyelinated afferents called C fibers. C fibers, sometimes classified as nociceptors, can detect various painful stimuli, including temperature extremes. However, it is increasingly evident that these afferents respond to various pruritic stimuli and transmit information to the brain that is perceived as itch; this can subsequently drive scratching behavior. Although itch and pain are distinct sensations, they are closely related and can, under certain circumstances, antagonize each other. However, it is not clear precisely when, where, and how the processes generating these two sensations originate and how they are dissociated. Clues have come from the analysis of the activities of specific ligands and their receptors. New data indicate that specific pruritic ligands carrying both itch and pain information are selectively recognized by different G protein–coupled receptors (GPCRs), and this information may be transduced through different intracellular circuits in the same neuron. These findings raise questions about the intracellular mechanisms that preprocess and perhaps encode GPCR-mediated signals.</p>","PeriodicalId":49560,"journal":{"name":"Science Signaling","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2011-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"30187058","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2010-11-19DOI: 10.1126/SCIENCE.330.6007.1019-A
P. Stern
The subunit composition of AMPA receptors at lateral amygdala synapses changes after the acquisition of associative fear. Inhibition of fear responses can be unexpectedly reversed even when a subject is perfectly safe. This can lead to inappropriate reactions to a fear-associated trigger, such as a bright light or loud noise. This type of reaction appears to underpin posttraumatic stress disorder, but there is little understanding of when training to inhibit fear may fail or succeed. Using a combination of electrophysiology and behavioral training in mice, Clem and Huganir observed that fear conditioning increased synaptic transmission by calcium-permeable AMPA receptors into the part of the brain that controls emotional responses (the amygdala). This effect lasted for about a week, during which the fearful memories could be erased if the animals were trained to reduce conditioned fear responses. Postmortem brain slices showed that the fear-induced synaptic changes also reversed, except in transgenic mice with a mutant subunit of the AMPA receptor. R. L. Clem, R. L. Huganir, Calcium-permeable AMPA receptor dynamics mediate fear memory erasure. Science 330, 1108–1112 (2010). [Abstract] [Full Text]
{"title":"Wiping Out Memories","authors":"P. Stern","doi":"10.1126/SCIENCE.330.6007.1019-A","DOIUrl":"https://doi.org/10.1126/SCIENCE.330.6007.1019-A","url":null,"abstract":"The subunit composition of AMPA receptors at lateral amygdala synapses changes after the acquisition of associative fear. Inhibition of fear responses can be unexpectedly reversed even when a subject is perfectly safe. This can lead to inappropriate reactions to a fear-associated trigger, such as a bright light or loud noise. This type of reaction appears to underpin posttraumatic stress disorder, but there is little understanding of when training to inhibit fear may fail or succeed. Using a combination of electrophysiology and behavioral training in mice, Clem and Huganir observed that fear conditioning increased synaptic transmission by calcium-permeable AMPA receptors into the part of the brain that controls emotional responses (the amygdala). This effect lasted for about a week, during which the fearful memories could be erased if the animals were trained to reduce conditioned fear responses. Postmortem brain slices showed that the fear-induced synaptic changes also reversed, except in transgenic mice with a mutant subunit of the AMPA receptor. R. L. Clem, R. L. Huganir, Calcium-permeable AMPA receptor dynamics mediate fear memory erasure. Science 330, 1108–1112 (2010). [Abstract] [Full Text]","PeriodicalId":49560,"journal":{"name":"Science Signaling","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2010-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78184061","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Tian-Rui Xu, Vladislav Vyshemirsky, Amélie Gormand, Alex von Kriegsheim, Mark Girolami, George S Baillie, Dominic Ketley, Allan J Dunlop, Graeme Milligan, Miles D Houslay, Walter Kolch
The specification of biological decisions by signaling pathways is encoded by the interplay between activation dynamics and network topologies. Although we can describe complex networks, we cannot easily determine which topology the cell actually uses to transduce a specific signal. Experimental testing of all plausible topologies is infeasible because of the combinatorially large number of experiments required to explore the complete hypothesis space. Here, we demonstrate that Bayesian inference-based modeling provides an approach to explore and constrain this hypothesis space,permitting the rational ranking of pathway models. Our approach can use measurements of a limited number of biochemical species when combined with multiple perturbations. As proof of concept, we examined the activation of the extracellular signal-regulated kinase (ERK) pathway by epidermal growth factor. The predicted and experimentally validated model shows that both Raf-1 and, unexpectedly,B-Raf are needed to fully activate ERK in two different cell lines. Thus, our formal methodology rationally infers evidentially supported pathway topologies even when a limited number of biochemical and kinetic measurements are available.
{"title":"Inferring signaling pathway topologies from multiple perturbation measurements of specific biochemical species.","authors":"Tian-Rui Xu, Vladislav Vyshemirsky, Amélie Gormand, Alex von Kriegsheim, Mark Girolami, George S Baillie, Dominic Ketley, Allan J Dunlop, Graeme Milligan, Miles D Houslay, Walter Kolch","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>The specification of biological decisions by signaling pathways is encoded by the interplay between activation dynamics and network topologies. Although we can describe complex networks, we cannot easily determine which topology the cell actually uses to transduce a specific signal. Experimental testing of all plausible topologies is infeasible because of the combinatorially large number of experiments required to explore the complete hypothesis space. Here, we demonstrate that Bayesian inference-based modeling provides an approach to explore and constrain this hypothesis space,permitting the rational ranking of pathway models. Our approach can use measurements of a limited number of biochemical species when combined with multiple perturbations. As proof of concept, we examined the activation of the extracellular signal-regulated kinase (ERK) pathway by epidermal growth factor. The predicted and experimentally validated model shows that both Raf-1 and, unexpectedly,B-Raf are needed to fully activate ERK in two different cell lines. Thus, our formal methodology rationally infers evidentially supported pathway topologies even when a limited number of biochemical and kinetic measurements are available.</p>","PeriodicalId":49560,"journal":{"name":"Science Signaling","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2010-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"29205816","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2009-08-25DOI: 10.1126/science.325_919e
P. Stern
Pharmacological and biochemical analyses reveal that dopamine determines the duration of fear memory storage. How can memory traces persist over days or weeks, despite the short-lived nature and rapid turnover of their molecular substrates? It has recently been reported that, in order to persist, an otherwise rapidly forgotten long-term memory requires BDNF (brain-derived neurotrophic factor) expression in the hippocampus 12 hours after training. Rossato et al. now show that this mechanism is gated into action by activation of the ventral tegmental area acting upon dopamine D1 receptors in the hippocampus. Time-limited N-methyl-D-aspartate receptor–dependent activity in the ventral tegmental area–hippocampal circuitry underlies the delayed increase in BDNF levels in the hippocampus 12 hours after inhibitory avoidance, a hippocampus-dependent form of learning. J. I. Rossato, L. R. M. Bevilaqua, I. Izquierdo, J. H. Medina, M. Cammarota, Dopamine controls persistence of long-term memory storage. Science 325, 1017–1020 (2009). [Abstract] [Full Text]
药理学和生化分析表明，多巴胺决定恐惧记忆储存的持续时间。记忆痕迹如何能持续数天或数周，尽管它们的分子底物短暂且快速更新?最近有报道称，为了保持长期记忆，在训练12小时后，海马中需要BDNF(脑源性神经营养因子)的表达。Rossato等人现在表明，这种机制是通过激活腹侧被盖区作用于海马体中的多巴胺D1受体而起作用的。在抑制性回避(一种海马依赖的学习形式)后12小时，腹侧被盖区-海马回路中有限的n -甲基-d -天冬氨酸受体依赖活性是海马BDNF水平延迟增加的基础。J. I. Rossato, L. R. M. Bevilaqua, I. Izquierdo, J. H. Medina, M. Cammarota，多巴胺控制长期记忆储存的持久性。科学学报，2009,37(2)。【摘要】【全文】
{"title":"Making Memories Last","authors":"P. Stern","doi":"10.1126/science.325_919e","DOIUrl":"https://doi.org/10.1126/science.325_919e","url":null,"abstract":"Pharmacological and biochemical analyses reveal that dopamine determines the duration of fear memory storage. How can memory traces persist over days or weeks, despite the short-lived nature and rapid turnover of their molecular substrates? It has recently been reported that, in order to persist, an otherwise rapidly forgotten long-term memory requires BDNF (brain-derived neurotrophic factor) expression in the hippocampus 12 hours after training. Rossato et al. now show that this mechanism is gated into action by activation of the ventral tegmental area acting upon dopamine D1 receptors in the hippocampus. Time-limited N-methyl-D-aspartate receptor–dependent activity in the ventral tegmental area–hippocampal circuitry underlies the delayed increase in BDNF levels in the hippocampus 12 hours after inhibitory avoidance, a hippocampus-dependent form of learning. J. I. Rossato, L. R. M. Bevilaqua, I. Izquierdo, J. H. Medina, M. Cammarota, Dopamine controls persistence of long-term memory storage. Science 325, 1017–1020 (2009). [Abstract] [Full Text]","PeriodicalId":49560,"journal":{"name":"Science Signaling","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2009-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89174011","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
扫码关注我们
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号