Pub Date : 2007-01-01DOI: 10.1101/087969767.48.345
D. Ron, H. Harding
Phosphorylation of the α subunit of eukaryotic translation initiation factor 2 (eIF2α) is a highly conserved regulatory event activated in response to diverse stresses (Chapter 12). It elicits translational reprogramming as its primary consequence and secondarily affects the transcriptional profile of cells (Chapter 9). Together, these two strands of the eIF2α phosphorylation-dependent integrated stress response (ISR) broadly affect gene expression, amino acid and energy metabolism, and the protein-folding environment in the cell. Rare human mutations and transgenic mice, in which components of the ISR have been severely altered, reveal the pathway’s importance to mammalian pathophysiology. Here, we review the components of the mammalian ISR and consider their function in the context of the cellular adaptation to protein mis-folding, nutrient deprivation, and other stresses. We address the potential importance of the ISR to such common human diseases as diabetes mellitus, the metabolic syndrome, osteoporosis, neurodegeneration, and demyelination. Special emphasis is placed on instances suggesting that failure of homeostasis in the ISR contributes to disease, and these are considered in the context of the hypothetical therapeutic opportunities they present. BACKGROUND Molecular and Physiological Principles That Determine the Consequences of eIF2α Phosphorylation Phosphorylation on serine 51 of its α subunit converts eIF2 from a substrate to an inhibitor of its guanine nucleotide exchange factor, eIF2B. Thus, the level of phosphorylated eIF2α regulates the rate at which eIF2 can be recycled to the GTP-bound form to join in a ternary complex with charged initiator methionyl-tRNA and promote the initiation of mRNA translation (Chapter 4).
{"title":"13 eIF2α Phosphorylation in Cellular Stress Responses and Disease","authors":"D. Ron, H. Harding","doi":"10.1101/087969767.48.345","DOIUrl":"https://doi.org/10.1101/087969767.48.345","url":null,"abstract":"Phosphorylation of the α subunit of eukaryotic translation initiation factor 2 (eIF2α) is a highly conserved regulatory event activated in response to diverse stresses (Chapter 12). It elicits translational reprogramming as its primary consequence and secondarily affects the transcriptional profile of cells (Chapter 9). Together, these two strands of the eIF2α phosphorylation-dependent integrated stress response (ISR) broadly affect gene expression, amino acid and energy metabolism, and the protein-folding environment in the cell. Rare human mutations and transgenic mice, in which components of the ISR have been severely altered, reveal the pathway’s importance to mammalian pathophysiology. Here, we review the components of the mammalian ISR and consider their function in the context of the cellular adaptation to protein mis-folding, nutrient deprivation, and other stresses. We address the potential importance of the ISR to such common human diseases as diabetes mellitus, the metabolic syndrome, osteoporosis, neurodegeneration, and demyelination. Special emphasis is placed on instances suggesting that failure of homeostasis in the ISR contributes to disease, and these are considered in the context of the hypothetical therapeutic opportunities they present. BACKGROUND Molecular and Physiological Principles That Determine the Consequences of eIF2α Phosphorylation Phosphorylation on serine 51 of its α subunit converts eIF2 from a substrate to an inhibitor of its guanine nucleotide exchange factor, eIF2B. Thus, the level of phosphorylated eIF2α regulates the rate at which eIF2 can be recycled to the GTP-bound form to join in a ternary complex with charged initiator methionyl-tRNA and promote the initiation of mRNA translation (Chapter 4).","PeriodicalId":10493,"journal":{"name":"Cold Spring Harbor Monograph Archive","volume":"64 1","pages":"345-368"},"PeriodicalIF":0.0,"publicationDate":"2007-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73443426","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The chemical senses, taste and smell, are ancient sensory modalities that allow animals to evaluate and interact with their environment and make adaptive decisions to enhance survival. The most primitive embodiment of chemical sensing can be seen in the orientation toward nutrients shown by single-celled prokaryotes (Berg 1975). Even some plants appear to have the capacity to detect air-borne chemical signals that allow them to orient toward food sources (Runyon et al. 2006). Smell and taste are used by higher animals to guide food and mate selection, and to avoid environmental dangers such as fires and noxious chemicals. Perhaps more than any other senses, smell and taste are perceptually intertwined. In humans, and presumably other animals, the “flavor” of food is a perfect fusion of our perception of the taste of the food and its smell. Olfaction allows animals to detect volatile chemicals at a distance, whereas gustation requires direct contact with the relevant chemical. Thus, the sense of smell can be used to orient toward attractive stimuli, such as palatable food or a suitable mate, and to orient away from repulsive stimuli, such as spoiled food or fire. Since taste requires contact with the stimulus, this sense is crucial for sensory evaluation immediately before ingestion. Foods that smell attractive but contain nonvolatile substances that make them inedible can be vetted by the gustatory system before ingestion. Most animals show appetitive responses to sugars and rejection behaviors to bitter or sour compounds, a likely outcome of many generations of selective...
化学感官，味觉和嗅觉，是古老的感官形式，使动物能够评估和与环境互动，并做出适应性决定，以提高生存能力。最原始的化学感知体现在单细胞原核生物对营养物质的定向中(Berg 1975)。甚至一些植物似乎也有能力探测空气中的化学信号，从而使它们能够找到食物来源(Runyon et al. 2006)。高等动物利用嗅觉和味觉来指导食物和配偶的选择，并避免火灾和有毒化学物质等环境危险。与其他感官相比，嗅觉和味觉在感知上可能更紧密地交织在一起。对人类来说，可能还有其他动物，食物的“味道”是我们对食物味道和气味的感知的完美融合。嗅觉使动物能够在一定距离内检测到挥发性化学物质，而味觉则需要直接接触到相关化学物质。因此，嗅觉可以被用来指向有吸引力的刺激，比如美味的食物或合适的伴侣，而远离令人反感的刺激，比如变质的食物或火。由于味觉需要与刺激物接触，因此这种感觉对于摄入之前的感官评估至关重要。那些闻起来很诱人但含有不可食用的非挥发性物质的食物可以在食用前经过味觉系统的审查。大多数动物对糖表现出食欲反应，对苦或酸的化合物表现出排斥行为，这可能是许多代选择性…
{"title":"4 Olfactory/Gustatory Processing","authors":"L. Vosshall","doi":"10.1101/087969819.49.79","DOIUrl":"https://doi.org/10.1101/087969819.49.79","url":null,"abstract":"The chemical senses, taste and smell, are ancient sensory modalities that allow animals to evaluate and interact with their environment and make adaptive decisions to enhance survival. The most primitive embodiment of chemical sensing can be seen in the orientation toward nutrients shown by single-celled prokaryotes (Berg 1975). Even some plants appear to have the capacity to detect air-borne chemical signals that allow them to orient toward food sources (Runyon et al. 2006). Smell and taste are used by higher animals to guide food and mate selection, and to avoid environmental dangers such as fires and noxious chemicals. Perhaps more than any other senses, smell and taste are perceptually intertwined. In humans, and presumably other animals, the “flavor” of food is a perfect fusion of our perception of the taste of the food and its smell. Olfaction allows animals to detect volatile chemicals at a distance, whereas gustation requires direct contact with the relevant chemical. Thus, the sense of smell can be used to orient toward attractive stimuli, such as palatable food or a suitable mate, and to orient away from repulsive stimuli, such as spoiled food or fire. Since taste requires contact with the stimulus, this sense is crucial for sensory evaluation immediately before ingestion. Foods that smell attractive but contain nonvolatile substances that make them inedible can be vetted by the gustatory system before ingestion. Most animals show appetitive responses to sugars and rejection behaviors to bitter or sour compounds, a likely outcome of many generations of selective...","PeriodicalId":10493,"journal":{"name":"Cold Spring Harbor Monograph Archive","volume":"137 1","pages":"79-100"},"PeriodicalIF":0.0,"publicationDate":"2007-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89311610","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2007-01-01DOI: 10.1101/087969767.48.655
A. Jacobson, E. Izaurralde
Mutations resulting in the loss of production of specific proteins are among the major causes of inherited diseases. When defective, any of several steps in the gene expression pathway can be the underlying cause of such diseases (Kazazian 1990), but one of the more common types of mutation that inactivates gene function does so by promoting premature translational termination. Nonsense mutations result in the occurrence of UAA, UAG, or UGA codons in the protein-coding region of an mRNA template, leading to the termination of polypeptide elongation and, generally, to the triggering of a cellular surveillance mechanism dubbed nonsense-mediated mRNA decay, or NMD. The NMD pathway is operative in all eukaryotic cells and ensures that nonsense-containing mRNAs do not accumulate as substrates for the translation apparatus. In turn, the elimination of these transcripts prevents the accumulation of potentially toxic polypeptide fragments. NMD has been extensively studied in yeast, worms, flies, and mammals, leading to the identification of a key set of regulatory factors and to the elaboration of models explaining the role of these factors in the discrimination of normal versus premature termination and in the promotion of rapid mRNA decay. These studies have provided insight into cellular quality control mechanisms, elucidated fundamental interrelationships between the pathways of mRNA translation and mRNA decay, and set the stage for a potentially major advance in the treatment of a subset of all genetic disorders. NORMAL VERSUS PREMATURE TRANSLATION TERMINATION Unlike initiation and elongation, which involve scores of factors, the events that take place...
{"title":"23 Nonsense-mediated mRNA Decay: From Yeast to Metazoans","authors":"A. Jacobson, E. Izaurralde","doi":"10.1101/087969767.48.655","DOIUrl":"https://doi.org/10.1101/087969767.48.655","url":null,"abstract":"Mutations resulting in the loss of production of specific proteins are among the major causes of inherited diseases. When defective, any of several steps in the gene expression pathway can be the underlying cause of such diseases (Kazazian 1990), but one of the more common types of mutation that inactivates gene function does so by promoting premature translational termination. Nonsense mutations result in the occurrence of UAA, UAG, or UGA codons in the protein-coding region of an mRNA template, leading to the termination of polypeptide elongation and, generally, to the triggering of a cellular surveillance mechanism dubbed nonsense-mediated mRNA decay, or NMD. The NMD pathway is operative in all eukaryotic cells and ensures that nonsense-containing mRNAs do not accumulate as substrates for the translation apparatus. In turn, the elimination of these transcripts prevents the accumulation of potentially toxic polypeptide fragments. NMD has been extensively studied in yeast, worms, flies, and mammals, leading to the identification of a key set of regulatory factors and to the elaboration of models explaining the role of these factors in the discrimination of normal versus premature termination and in the promotion of rapid mRNA decay. These studies have provided insight into cellular quality control mechanisms, elucidated fundamental interrelationships between the pathways of mRNA translation and mRNA decay, and set the stage for a potentially major advance in the treatment of a subset of all genetic disorders. NORMAL VERSUS PREMATURE TRANSLATION TERMINATION Unlike initiation and elongation, which involve scores of factors, the events that take place...","PeriodicalId":10493,"journal":{"name":"Cold Spring Harbor Monograph Archive","volume":"32 1","pages":"655-687"},"PeriodicalIF":0.0,"publicationDate":"2007-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81768566","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2007-01-01DOI: 10.1101/087969752.50.667
T. Alliston, E. Piek, R. Derynck
The transforming growth factor-β (TGF-β) family is critically involved in the development and maintenance of skeletal tissues. In searches for factors with potent cartilage and bone inductive activities, TGF-β was isolated as cartilage-inducing factor (Seyedin et al. 1987), whereas bone morphogenetic proteins (BMPs) were isolated as factors able to induce cartilage and bone formation (Urist 1965; Luyten et al. 1989). The TGF-β family shows extensive redundancy of ligands, receptors, agonists, and antagonists, yet the diverse temporal and spatial patterns of expression of each pathway component allow these signaling factors to direct skeletal development and homeostasis by regulating patterning, cell-fate determination, cell differentiaton, and bone remodeling. The critical roles of each factor are evident in mice with mutations in components of these pathways, whereas in vitro studies have elucidated the mechanisms for the action of the TGF-β family in mesenchymal and skeletal cells. Because the TGF-β family has a central role in the regulation of mesenchymal differentiation into skeletal cells, its role in osteoblast and chondrocyte development is detailed in Chapter 21. Here we discuss, at the tissue level, the impact of TGF-β family ligands and signaling pathways in skeletal patterning, skeletal development, and skeletal maintenance and metabolism, as well as the effects of their deregulation in many skeletal diseases. IMPLICATION AND LOCALIZATION OF TGF-β FAMILY SIGNALING COMPONENTS IN THE SKELETON Many members of the TGF-β family, their receptors, and signaling effectors, the Smads, are widely expressed in mesenchymal tissues throughout development and, in particular, at sites of skeletal patterning and...
转化生长因子-β (TGF-β)家族在骨组织的发育和维持中起关键作用。在寻找具有强软骨和骨诱导活性的因子时，TGF-β被分离为软骨诱导因子(Seyedin et al. 1987)，而骨形态发生蛋白(BMPs)被分离为能够诱导软骨和骨形成的因子(Urist 1965;Luyten et al. 1989)。TGF-β家族显示出广泛的配体、受体、激动剂和拮抗剂的冗余，然而每个通路组分的不同时空表达模式允许这些信号因子通过调节模式、细胞命运决定、细胞分化和骨重塑来指导骨骼发育和体内平衡。每种因子的关键作用在这些通路组分发生突变的小鼠中都是明显的，而体外研究已经阐明了TGF-β家族在间充质细胞和骨骼细胞中的作用机制。由于TGF-β家族在调节间充质细胞分化为骨骼细胞中起核心作用，其在成骨细胞和软骨细胞发育中的作用将在第21章中详细介绍。在这里，我们在组织水平上讨论TGF-β家族配体和信号通路在骨骼模式、骨骼发育、骨骼维持和代谢中的影响，以及它们在许多骨骼疾病中的失调作用。TGF-β家族信号成分在骨骼中的意义和定位TGF-β家族的许多成员，它们的受体和信号效应器，Smads，在整个发育过程中广泛表达于间质组织中，特别是在骨骼模式和…
{"title":"22 TGF-β Family Signaling in Skeletal Development, Maintenance, and Disease","authors":"T. Alliston, E. Piek, R. Derynck","doi":"10.1101/087969752.50.667","DOIUrl":"https://doi.org/10.1101/087969752.50.667","url":null,"abstract":"The transforming growth factor-β (TGF-β) family is critically involved in the development and maintenance of skeletal tissues. In searches for factors with potent cartilage and bone inductive activities, TGF-β was isolated as cartilage-inducing factor (Seyedin et al. 1987), whereas bone morphogenetic proteins (BMPs) were isolated as factors able to induce cartilage and bone formation (Urist 1965; Luyten et al. 1989). The TGF-β family shows extensive redundancy of ligands, receptors, agonists, and antagonists, yet the diverse temporal and spatial patterns of expression of each pathway component allow these signaling factors to direct skeletal development and homeostasis by regulating patterning, cell-fate determination, cell differentiaton, and bone remodeling. The critical roles of each factor are evident in mice with mutations in components of these pathways, whereas in vitro studies have elucidated the mechanisms for the action of the TGF-β family in mesenchymal and skeletal cells. Because the TGF-β family has a central role in the regulation of mesenchymal differentiation into skeletal cells, its role in osteoblast and chondrocyte development is detailed in Chapter 21. Here we discuss, at the tissue level, the impact of TGF-β family ligands and signaling pathways in skeletal patterning, skeletal development, and skeletal maintenance and metabolism, as well as the effects of their deregulation in many skeletal diseases. IMPLICATION AND LOCALIZATION OF TGF-β FAMILY SIGNALING COMPONENTS IN THE SKELETON Many members of the TGF-β family, their receptors, and signaling effectors, the Smads, are widely expressed in mesenchymal tissues throughout development and, in particular, at sites of skeletal patterning and...","PeriodicalId":10493,"journal":{"name":"Cold Spring Harbor Monograph Archive","volume":"26 1","pages":"667-723"},"PeriodicalIF":0.0,"publicationDate":"2007-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82632660","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2007-01-01DOI: 10.1101/087969819.49.581
R. Meech, G. Mackie
All forms of life exhibit excitability; it is one of the characteristics by which living creatures can be recognized. In this chapter, we examine the different manifestations of excitability exhibited by the Metazoa and show how elements present in the Bacteria come together in the Protozoa, Porifera, Cnidaria, and Ctenophora (see Fig. 1) to form the patterns of excitability known as “behavior.” We consider the role of excitation in fertilized eggs and conducting epithelia, as well as the origins of signaling in nerves and muscles. We describe different forms of all-or-nothing signaling, as well as ways of generating graded responsiveness. This study attempts to provide a practical approach to understanding the limitations of excitable systems. We believe that defining these limits is more useful than glorifying their seemingly endless sophistication. THE NATURE OF EXCITABILITY Excitability Defined Excitability is easy to recognize; less easy to define. We recognize excitability when we see it, by the way an organism responds to an external stimulus. For there to be a response, stimulus and organism must interact and the organism must “receive” the stimulus. Inevitably, the stimulus site, or receptor, and the response site, or effector, will be at different locations even in single cells. Thus, excitability depends on the transmission of signals from receptor to effector. The signals may be chemical and spread by passive diffusion, electrical and spread by the transfer of ionic charge, or mechanical and spread by a physical disturbance. We focus in this section on the links between chemical...
{"title":"Evolution of excitability in lower metazoans","authors":"R. Meech, G. Mackie","doi":"10.1101/087969819.49.581","DOIUrl":"https://doi.org/10.1101/087969819.49.581","url":null,"abstract":"All forms of life exhibit excitability; it is one of the characteristics by which living creatures can be recognized. In this chapter, we examine the different manifestations of excitability exhibited by the Metazoa and show how elements present in the Bacteria come together in the Protozoa, Porifera, Cnidaria, and Ctenophora (see Fig. 1) to form the patterns of excitability known as “behavior.” We consider the role of excitation in fertilized eggs and conducting epithelia, as well as the origins of signaling in nerves and muscles. We describe different forms of all-or-nothing signaling, as well as ways of generating graded responsiveness. This study attempts to provide a practical approach to understanding the limitations of excitable systems. We believe that defining these limits is more useful than glorifying their seemingly endless sophistication. THE NATURE OF EXCITABILITY Excitability Defined Excitability is easy to recognize; less easy to define. We recognize excitability when we see it, by the way an organism responds to an external stimulus. For there to be a response, stimulus and organism must interact and the organism must “receive” the stimulus. Inevitably, the stimulus site, or receptor, and the response site, or effector, will be at different locations even in single cells. Thus, excitability depends on the transmission of signals from receptor to effector. The signals may be chemical and spread by passive diffusion, electrical and spread by the transfer of ionic charge, or mechanical and spread by a physical disturbance. We focus in this section on the links between chemical...","PeriodicalId":10493,"journal":{"name":"Cold Spring Harbor Monograph Archive","volume":"31 1","pages":"581-616"},"PeriodicalIF":0.0,"publicationDate":"2007-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78766242","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2007-01-01DOI: 10.1101/087969819.49.123
E. Warrant, A. Kelber, Rikard Frederiksen
The arthropods constitute the largest single phylum of the animal kingdom and, with almost a million known species, more than three-quarters of all animal species. The insects and crustaceans alone account for nearly all arthropods, and their compound eyes are thus the most numerous and widespread eye design found on Earth. Not surprisingly, the great adaptability and versatility of arthropods, and their conquest of almost every conceivable habitat, have led to the evolution of a remarkable range of visual specializations, both peripherally in the eyes themselves and centrally in the brain centers responsible for the higher processing of visual information. The compound eyes of insects, crustaceans, and the horseshoe crab Limulus (a xiphosurid chelicerate) are composed of individual optical units known as ommatidia (Fig. 1A). Each of these generally contains one or more lenses (the dioptric apparatus) that capture and focus the incoming light and a number of photoreceptors that together act as an optical waveguide, within which the light propagates and is absorbed. Visual pigment (rhodopsin) molecules, densely packed within the microvillar membranes of the waveguide, convert the absorbed light energy into an electrical signal—the visual response—that is carried by the photoreceptor axons to higher levels in the visual system for further processing. Exactly which qualities of light lead to an electrical signal depends on a number of factors—both morphological and physiological—that are inherent within each ommatidium, and these differ markedly from species to species according to lifestyle and habitat. The sensitivity of the eye...
{"title":"6 Ommatidial Adaptations for Spatial, Spectral, and Polarization Vision in Arthropods","authors":"E. Warrant, A. Kelber, Rikard Frederiksen","doi":"10.1101/087969819.49.123","DOIUrl":"https://doi.org/10.1101/087969819.49.123","url":null,"abstract":"The arthropods constitute the largest single phylum of the animal kingdom and, with almost a million known species, more than three-quarters of all animal species. The insects and crustaceans alone account for nearly all arthropods, and their compound eyes are thus the most numerous and widespread eye design found on Earth. Not surprisingly, the great adaptability and versatility of arthropods, and their conquest of almost every conceivable habitat, have led to the evolution of a remarkable range of visual specializations, both peripherally in the eyes themselves and centrally in the brain centers responsible for the higher processing of visual information. The compound eyes of insects, crustaceans, and the horseshoe crab Limulus (a xiphosurid chelicerate) are composed of individual optical units known as ommatidia (Fig. 1A). Each of these generally contains one or more lenses (the dioptric apparatus) that capture and focus the incoming light and a number of photoreceptors that together act as an optical waveguide, within which the light propagates and is absorbed. Visual pigment (rhodopsin) molecules, densely packed within the microvillar membranes of the waveguide, convert the absorbed light energy into an electrical signal—the visual response—that is carried by the photoreceptor axons to higher levels in the visual system for further processing. Exactly which qualities of light lead to an electrical signal depends on a number of factors—both morphological and physiological—that are inherent within each ommatidium, and these differ markedly from species to species according to lifestyle and habitat. The sensitivity of the eye...","PeriodicalId":10493,"journal":{"name":"Cold Spring Harbor Monograph Archive","volume":"66 1","pages":"123-154"},"PeriodicalIF":0.0,"publicationDate":"2007-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77666553","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2007-01-01DOI: 10.1101/087969819.49.281
M. Giurfa
Cognitive science has become fashionable in recent years: A simple search for the word “cognition” in scientific databases will show the extent to which the scientific literature has incorporated a term that 10 years ago was rarely used. From psychological and philosophical studies to neurobiological studies, from modeling and robotics to ethological studies, from ecology to molecular biology, the word cognition can be found almost everywhere, because cognitive science has acquired a new dimension that reflects our growing interest in essential problems like consciousness, brain processing, and the emergence of thinking. Despite this diversity and increasing interest, a general definition for the term cognition remains elusive, probably because the approaches that characterize cognitive studies are diverse and still looking for a synthesis. Indeed, the term cognition may encompass concepts as diverse as human thinking and intelligence, functions leading to the acquisition and generation of meaning in explicit form, and basic perceptual processes (Wullimann and Roth 2001). Broader definitions have been proposed to include processes of acquisition and manipulation of information, attention, perception, decision making, learning, and memory (Shettleworth 1998Shettleworth 2001). In this chapter, I survey the evidence that such concepts can be applied in invertebrates. To provide an operational framework for this survey, I confine the use of the term cognition to complex forms of associative learning. In particular, because the term “complex” is also meaningless if it is not referred to a certain level of simplicity, I focus on nonelemental forms of associative learning —learning forms in which simple,...
{"title":"12 Invertebrate Cognition: Nonelemental Learning beyond Simple Conditioning","authors":"M. Giurfa","doi":"10.1101/087969819.49.281","DOIUrl":"https://doi.org/10.1101/087969819.49.281","url":null,"abstract":"Cognitive science has become fashionable in recent years: A simple search for the word “cognition” in scientific databases will show the extent to which the scientific literature has incorporated a term that 10 years ago was rarely used. From psychological and philosophical studies to neurobiological studies, from modeling and robotics to ethological studies, from ecology to molecular biology, the word cognition can be found almost everywhere, because cognitive science has acquired a new dimension that reflects our growing interest in essential problems like consciousness, brain processing, and the emergence of thinking. Despite this diversity and increasing interest, a general definition for the term cognition remains elusive, probably because the approaches that characterize cognitive studies are diverse and still looking for a synthesis. Indeed, the term cognition may encompass concepts as diverse as human thinking and intelligence, functions leading to the acquisition and generation of meaning in explicit form, and basic perceptual processes (Wullimann and Roth 2001). Broader definitions have been proposed to include processes of acquisition and manipulation of information, attention, perception, decision making, learning, and memory (Shettleworth 1998Shettleworth 2001). In this chapter, I survey the evidence that such concepts can be applied in invertebrates. To provide an operational framework for this survey, I confine the use of the term cognition to complex forms of associative learning. In particular, because the term “complex” is also meaningless if it is not referred to a certain level of simplicity, I focus on nonelemental forms of associative learning —learning forms in which simple,...","PeriodicalId":10493,"journal":{"name":"Cold Spring Harbor Monograph Archive","volume":"9 1","pages":"281-308"},"PeriodicalIF":0.0,"publicationDate":"2007-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"72862992","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2007-01-01DOI: 10.1101/087969767.48.829
P. Fox, P. S. Ray, A. Arif, J. Jia
Aminoacyl-tRNA synthetases (AARSs) are ancient enzymes, ubiquitous in the three domains of life, that catalyze the ligation of amino acids to cognate tRNAs (Ibba and Soll 2000; Ribas de Pouplana and Schimmel 2001). They are uniquely responsible for deciphering the genetic code, reading the genetic information in the tRNA anticodon, and ligating the appropriate amino acid to the terminal ribose of the conserved CCA sequence at the 3′ end of the tRNA. In most prokaryotes, there are 20 AARSs, one for each major amino acid. Lower eukaryotes have separate cytoplasmic and nuclear-encoded mitochondrial (as well as chloroplastic) AARSs (Sissler et al. 2005). In all vertebrates, and in some invertebrates, the 20 cytoplasmic AARS activities are contained in 19 proteins; the bifunctional GluProRS expresses two enzyme activities in a single polypeptide chain. All synthetases contain catalytic and tRNA anticodon recognition sites in separate domains, and belong to one of two structurally distinct classes (Ibba and Soll 2000). The 10 Class I enzymes have a Rossman fold in the active site, bind the minor groove of the tRNA acceptor stem, and aminoacylate ribose at the 2′-OH position. In contrast, the 10 Class II enzymes have an antiparallel β-sheet in the active site, bind the major groove of the acceptor stem, and aminoacylate ribose at 3′-OH. Class I and II enzymes can be further grouped into subclasses that exhibit additional structural similarities and that recognize related amino acid substrates. In vertebrate cells, 9 AARS activities in 8 enzymes (including the bifunctional GluProRS, also...
氨基酰基trna合成酶(AARSs)是一种古老的酶，普遍存在于生命的三个领域，催化氨基酸连接到同源trna (Ibba and Soll 2000;Ribas de Pouplana and Schimmel 2001)。它们负责破译遗传密码，读取tRNA反密码子中的遗传信息，并将适当的氨基酸连接到tRNA 3 '端的保守CCA序列的末端核糖上。在大多数原核生物中，有20个aars，每个主要氨基酸对应一个aars。低级真核生物有独立的细胞质和核编码线粒体(以及叶绿体)aars (Sissler et al. 2005)。在所有脊椎动物和一些无脊椎动物中，20种细胞质AARS活性包含在19种蛋白质中;双功能的gluproors在一个多肽链中表达两种酶的活性。所有合成酶都在不同的结构域含有催化和tRNA反密码子识别位点，属于两种结构不同的类别之一(Ibba和Soll 2000)。10种I类酶在活性位点具有Rossman折叠，结合tRNA受体茎的小槽，并在2 ' -OH位置氨基酰化核糖。相比之下，10种II类酶在活性位点具有反平行的β-片，结合受体茎的主要凹槽，并在3 ' -OH上氨基酰化核糖。I类和II类酶可以进一步分为具有额外结构相似性和识别相关氨基酸底物的亚类。在脊椎动物细胞中，9种AARS在8种酶中具有活性(包括双功能的GluProRS，也…
{"title":"29 Noncanonical Functions of Aminoacyl-tRNA Synthetases in Translational Control","authors":"P. Fox, P. S. Ray, A. Arif, J. Jia","doi":"10.1101/087969767.48.829","DOIUrl":"https://doi.org/10.1101/087969767.48.829","url":null,"abstract":"Aminoacyl-tRNA synthetases (AARSs) are ancient enzymes, ubiquitous in the three domains of life, that catalyze the ligation of amino acids to cognate tRNAs (Ibba and Soll 2000; Ribas de Pouplana and Schimmel 2001). They are uniquely responsible for deciphering the genetic code, reading the genetic information in the tRNA anticodon, and ligating the appropriate amino acid to the terminal ribose of the conserved CCA sequence at the 3′ end of the tRNA. In most prokaryotes, there are 20 AARSs, one for each major amino acid. Lower eukaryotes have separate cytoplasmic and nuclear-encoded mitochondrial (as well as chloroplastic) AARSs (Sissler et al. 2005). In all vertebrates, and in some invertebrates, the 20 cytoplasmic AARS activities are contained in 19 proteins; the bifunctional GluProRS expresses two enzyme activities in a single polypeptide chain. All synthetases contain catalytic and tRNA anticodon recognition sites in separate domains, and belong to one of two structurally distinct classes (Ibba and Soll 2000). The 10 Class I enzymes have a Rossman fold in the active site, bind the minor groove of the tRNA acceptor stem, and aminoacylate ribose at the 2′-OH position. In contrast, the 10 Class II enzymes have an antiparallel β-sheet in the active site, bind the major groove of the acceptor stem, and aminoacylate ribose at 3′-OH. Class I and II enzymes can be further grouped into subclasses that exhibit additional structural similarities and that recognize related amino acid substrates. In vertebrate cells, 9 AARS activities in 8 enzymes (including the bifunctional GluProRS, also...","PeriodicalId":10493,"journal":{"name":"Cold Spring Harbor Monograph Archive","volume":"79 1","pages":"829-854"},"PeriodicalIF":0.0,"publicationDate":"2007-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87106449","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2007-01-01DOI: 10.1101/087969767.48.319
T. Dever, A. Dar, F. Sicheri
Perhaps the best-characterized mechanism of translational control in eukaryotic cells involves phosphorylation of eukaryotic translation initiation factor eIF2. As described in Chapters 4 and 9, eIF2, consisting of three subunits, α, β, and γ, specifically binds the initiator methionyl-tRNA (Met-tRNA i Met ) in a GTP-dependent manner and delivers this essential component of translation initiation to the small ribosomal subunit. The γ-subunit of eIF2 is responsible for GTP binding, and like other GTP-binding proteins, eIF2 cycles between its GTP-bound state and its GDP-bound state. The recycling of inactive eIF2•GDP to active eIF2•GTP is catalyzed by the guanine nucleotide exchange factor eIF2B. It is this recycling reaction that is regulated by phosphorylation of eIF2. Phosphorylation of Ser-51 in mature eIF2α converts eIF2 from a substrate to a competitive inhibitor of eIF2B. (It is noteworthy that according to the DNA sequence, the phosphorylation site in eIF2α is Ser-52. However, because the initiating Met of eIF2α is posttranslationally cleaved, the phosphorylated residue is Ser-51 in the mature protein.) This phosphorylation of eIF2α enhances its interaction with a trimeric regulatory eIF2Bαβδ subcomplex that can be biochemically separated from the pentameric eIF2B complex (Chapter 9). In all cells examined, the amount of eIF2B is limiting compared to the amount of eIF2. As a consequence, phosphorylation of a small percentage of eIF2α results in the apparent sequestration of eIF2B in inactive phosphorylated eIF2•eIF2B complexes and in the inhibition of protein synthesis. Initially, eIF2 phosphorylation was linked to the shut-off of protein synthesis in heme-deprived or double-stranded RNA (dsRNA)-treated rabbit...
也许真核细胞中翻译控制最具特征的机制涉及真核翻译起始因子eIF2的磷酸化。如第4章和第9章所述，eIF2由三个亚基，α， β和γ组成，以gtp依赖的方式特异性地结合启动物甲硫基trna (Met- trna i Met)，并将翻译起始的重要组成部分传递给小核糖体亚基。eIF2的γ-亚基负责GTP结合，与其他GTP结合蛋白一样，eIF2在GTP结合状态和gdp结合状态之间循环。在鸟嘌呤核苷酸交换因子eIF2B的催化下，无活性eIF2•GDP再循环为有活性的eIF2•GTP。正是这种循环反应受到eIF2磷酸化的调控。成熟eIF2α中Ser-51的磷酸化将eIF2从底物转化为eIF2B的竞争性抑制剂。(值得注意的是，根据DNA序列，eIF2α的磷酸化位点为Ser-52。然而，由于eIF2α的起始Met是翻译后切割的，因此在成熟蛋白中磷酸化的残基是Ser-51。eIF2α的磷酸化增强了其与三聚体调节eIF2Bαβδ亚复合物的相互作用，该亚复合物可以从五聚体eIF2B复合物中生化分离出来(第9章)。在所有检测的细胞中，与eIF2的量相比，eIF2B的量是有限的。因此，一小部分eIF2α的磷酸化导致eIF2B在无活性磷酸化的eIF2•eIF2B复合物中明显被隔离，并抑制蛋白质合成。最初，eIF2磷酸化与血红素剥夺或双链RNA (dsRNA)处理家兔的蛋白质合成关闭有关。
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Pub Date : 2007-01-01DOI: 10.1101/087969819.49.347
D. Glanzman
Although it has been formally recognized since the end of the 19th century that invertebrates can learn (Romanes 1895), the modern neurobiological analysis of invertebrate learning did not begin until the 1960s. Starting in that decade, pioneering investigators began to use intracellular electrophysiology to probe the basic mechanisms of learning in higher invertebrates (Bruner and Tauc 1966; Kandel 1967; Krasne 1969). Initially, these studies focused on simple forms of nonassociative learning, including habituation and sensitization. However, by the early 1980s, associative learning, particularly classical conditioning, had been described in several invertebrate systems that were amenable to electrophysiological and biochemical—and, in the case of Drosophila, genetic—analyses (Takeda 1961; Henderson and Strong 1972; Mpitsos and Davis 1973; Menzel et al. 1974; Dudai et al. 1976; Crow and Alkon 1978; Chang and Gelperin 1980; Hoyle 1980; Carew et al. 1981; Lukowiak and Sahley 1981). Research on learning and memory in invertebrates during the past four decades has yielded fundamental insights into our understanding of the changes that take place within an animal’s nervous system when it learns. The major advantage of invertebrate systems for cell biological analyses of learning and memory is the relative simplicity of their nervous systems. Many higher invertebrates possess only 10,000–100,000 neurons. Although still great, this sum is dwarfed by the billions of neurons in the brains of mammals. Furthermore, invertebrate nervous systems characteristically possess so-called identified neurons. These are neurons whose size, position, electrical properties, basic synaptic connections, and physiological and behavioral functions are more...
尽管自19世纪末以来，无脊椎动物可以学习(Romanes 1895)已被正式承认，但对无脊椎动物学习的现代神经生物学分析直到20世纪60年代才开始。从那十年开始，开创性的研究人员开始使用细胞内电生理学来探索高等无脊椎动物学习的基本机制(Bruner和Tauc 1966;坎德尔1967;Krasne 1969)。最初，这些研究集中在非联想学习的简单形式，包括习惯化和敏化。然而，到20世纪80年代初，联想学习，特别是经典条件反射，已经在一些无脊椎动物系统中被描述为符合电生理和生化的，在果蝇的情况下，遗传分析(Takeda 1961;亨德森和斯特朗1972;Mpitsos和Davis, 1973;Menzel et al. 1974;Dudai et al. 1976;Crow and Alkon 1978;Chang and Gelperin 1980;霍伊尔1980;Carew et al. 1981;Lukowiak and Sahley 1981)。在过去的四十年里，对无脊椎动物学习和记忆的研究已经为我们理解动物神经系统在学习时发生的变化提供了基本的见解。对学习和记忆进行细胞生物学分析的无脊椎动物系统的主要优势是它们的神经系统相对简单。许多高等无脊椎动物只有1万到10万个神经元。尽管这个数字仍然很大，但与哺乳动物大脑中数十亿的神经元相比，这个数字就相形见绌了。此外，无脊椎动物的神经系统具有所谓的已识别神经元的特征。这些神经元的大小、位置、电特性、基本突触连接以及生理和行为功能……
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