Pub Date : 2008-10-07DOI: 10.1002/9780470032244.CH4
G. Burnstock
A brief account of the early history of extracellular signalling by ATP will be followed by a summary of the current subclassification of receptors for purines and pyrimidines. On the basis of cloning, transduction mechanisms and pharmacology, the P1 (adenosine) receptor family has 4 subtypes, while the P2 (ATP, ADP and UTP) receptor family has been divided into P2X ionotropic receptors (7 subtypes) and P2Y metabotropic G protein-coupled receptors (8 subtypes). The distribution of purinoceptors in both neuronal and non-neuronal cells and the physiology and pathophysiology of purinergic signalling will be reviewed. Examples of fast purinergic signalling include cotransmission and neuromodulation, exocrine and endocrine secretion, platelet aggregation, vascular endothelial cell-mediated vasodilatation and nociceptive mechanosensory transduction. Examples of slow (trophic) purinergic signalling include cell proliferation, differentiation and apoptosis in embryological development, neural regeneration, bone resorption, cell turnover of epithelial cells in skin and visceral organs, inflammation, wound healing and cancer. Finally the purinoceptor subtypes expressed on astrocytes, oligodendrocytes, Schwann cells, microglia, Müller cells and enteric glial cells will be summarized as well as evidence for non-lytic release of ATP from glial cells.
{"title":"Purinergic signalling--an overview.","authors":"G. Burnstock","doi":"10.1002/9780470032244.CH4","DOIUrl":"https://doi.org/10.1002/9780470032244.CH4","url":null,"abstract":"A brief account of the early history of extracellular signalling by ATP will be followed by a summary of the current subclassification of receptors for purines and pyrimidines. On the basis of cloning, transduction mechanisms and pharmacology, the P1 (adenosine) receptor family has 4 subtypes, while the P2 (ATP, ADP and UTP) receptor family has been divided into P2X ionotropic receptors (7 subtypes) and P2Y metabotropic G protein-coupled receptors (8 subtypes). The distribution of purinoceptors in both neuronal and non-neuronal cells and the physiology and pathophysiology of purinergic signalling will be reviewed. Examples of fast purinergic signalling include cotransmission and neuromodulation, exocrine and endocrine secretion, platelet aggregation, vascular endothelial cell-mediated vasodilatation and nociceptive mechanosensory transduction. Examples of slow (trophic) purinergic signalling include cell proliferation, differentiation and apoptosis in embryological development, neural regeneration, bone resorption, cell turnover of epithelial cells in skin and visceral organs, inflammation, wound healing and cancer. Finally the purinoceptor subtypes expressed on astrocytes, oligodendrocytes, Schwann cells, microglia, Müller cells and enteric glial cells will be summarized as well as evidence for non-lytic release of ATP from glial cells.","PeriodicalId":19323,"journal":{"name":"Novartis Foundation Symposium","volume":"276 1","pages":"26-48; discussion 48-57, 275-81"},"PeriodicalIF":0.0,"publicationDate":"2008-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"51134353","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 : 2008-10-07DOI: 10.1002/9780470035399.CH13
J. Sheehan, M. Kesimer, R. Pickles
Many of the proteins associated with innate immunity in the upper respiratory tract are to be found localized into mucus gels and the mucin-rich surface layers of the epithelium and the cilia. Mucus is a relatively dilute suspension of such macromolecules being around 2-4% solids in normal induced sputum. These proteins scavenge, immobilise and/or kill pathogens and at the same time immobilize them into the mucus. Mucus is moved from the lung by the mucociliary clearance mechanisms or by cough. Some 190 proteins are readily detectable in sputum by proteomics methods and about 100 in bronchial air-liquid interface culture secretions. This cell culture system mimics the surface ciliated phenotype of the large airways very well and about 85 secreted proteins are common to both culture and sputum secretions. The major single protein by weight in cell culture secretions is MUC5B and in sputum a mixture of MUC5B and MUC5AC. The three epithelial mucins MUC1, 4 and 16 are also detectable in both secretions. In this paper the roles that these molecules play in protecting and stabilising the ciliated surface and building the gel will be discussed. The role of water and ion homeostasis is particularly crucial in mucus gel formation and evidence is gathering that it is perturbation of hydration mechanisms that may play into defective mucus leading subsequently to stasis and mechanical problems.
{"title":"Innate immunity and mucus structure and function.","authors":"J. Sheehan, M. Kesimer, R. Pickles","doi":"10.1002/9780470035399.CH13","DOIUrl":"https://doi.org/10.1002/9780470035399.CH13","url":null,"abstract":"Many of the proteins associated with innate immunity in the upper respiratory tract are to be found localized into mucus gels and the mucin-rich surface layers of the epithelium and the cilia. Mucus is a relatively dilute suspension of such macromolecules being around 2-4% solids in normal induced sputum. These proteins scavenge, immobilise and/or kill pathogens and at the same time immobilize them into the mucus. Mucus is moved from the lung by the mucociliary clearance mechanisms or by cough. Some 190 proteins are readily detectable in sputum by proteomics methods and about 100 in bronchial air-liquid interface culture secretions. This cell culture system mimics the surface ciliated phenotype of the large airways very well and about 85 secreted proteins are common to both culture and sputum secretions. The major single protein by weight in cell culture secretions is MUC5B and in sputum a mixture of MUC5B and MUC5AC. The three epithelial mucins MUC1, 4 and 16 are also detectable in both secretions. In this paper the roles that these molecules play in protecting and stabilising the ciliated surface and building the gel will be discussed. The role of water and ion homeostasis is particularly crucial in mucus gel formation and evidence is gathering that it is perturbation of hydration mechanisms that may play into defective mucus leading subsequently to stasis and mechanical problems.","PeriodicalId":19323,"journal":{"name":"Novartis Foundation Symposium","volume":"279 1","pages":"155-66; discussion 167-9, 216-9"},"PeriodicalIF":0.0,"publicationDate":"2008-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"51137297","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}
Neural coding in the retina and lamina of fly compound eyes is amenable to detailed anatomical, physiological and theoretical analysis. This approach shows how identified cell signalling systems are optimized to maximize the transmission of information. Optimization reveals three familiar constraints, noise, saturation and bandwidth, and shows how coding can minimize their effects. Experiments reveal a fourth constraint, metabolic cost, whose properties favour the distribution of information among multiple pathways. The advantages of distributed codes will be offset by increasing complexity and the build up of noise. The optimization of coding in fly retina suggests that both noise and complexity will be reduced by matching each step in the system's operations to the input signal, and to the logical requirements of the network's ultimate function, pattern processing. This line of argument suggests tightly organized networks, laid out that information flows freely and independently, yet patterned so that the necessary contacts and transactions are made quickly and efficiently.
{"title":"Efficiency and complexity in neural coding.","authors":"S. Laughlin","doi":"10.1002/0470846674.CH14","DOIUrl":"https://doi.org/10.1002/0470846674.CH14","url":null,"abstract":"Neural coding in the retina and lamina of fly compound eyes is amenable to detailed anatomical, physiological and theoretical analysis. This approach shows how identified cell signalling systems are optimized to maximize the transmission of information. Optimization reveals three familiar constraints, noise, saturation and bandwidth, and shows how coding can minimize their effects. Experiments reveal a fourth constraint, metabolic cost, whose properties favour the distribution of information among multiple pathways. The advantages of distributed codes will be offset by increasing complexity and the build up of noise. The optimization of coding in fly retina suggests that both noise and complexity will be reduced by matching each step in the system's operations to the input signal, and to the logical requirements of the network's ultimate function, pattern processing. This line of argument suggests tightly organized networks, laid out that information flows freely and independently, yet patterned so that the necessary contacts and transactions are made quickly and efficiently.","PeriodicalId":19323,"journal":{"name":"Novartis Foundation Symposium","volume":"11 4","pages":"177-87; discussion 187-92, 234-40"},"PeriodicalIF":0.0,"publicationDate":"2008-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/0470846674.CH14","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"50767415","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}
Transplanted human embryonic dopamine neurons reinnervate the striatum in patients with Parkinson's disease. The grafts can exhibit long-term survival without immunological rejection and despite an ongoing disease process and continuous antiparkinsonian drug treatment. Recent findings using positron emission tomography indicate that the grafts are functionally integrated in the patient's brain and release dopamine into the striatum. In the most successful cases, patients have been able to withdraw L-dopa treatment after transplantation and resume an independent life. About two-thirds of grafted patients have shown clinically useful, partial recovery of motor function: increased percentage of time in the 'on'-phase and reduced rigidity and hypokinesia during 'off'-phases, bilaterally but predominantly on the side contralateral to the graft. Gait, speed, balance and dyskinesias have not exhibited any major, consistent improvements. Current research aims at solving three main problems: (a) large amounts of human embryonic mesencephalic tissue are needed for therapeutic effects; (b) symptomatic relief is incomplete and varies between patients; and (c) patient selection and grafting procedure have not been optimized.
{"title":"Neural transplantation in Parkinson's disease.","authors":"O. Lindvall","doi":"10.1002/0470870834.CH7","DOIUrl":"https://doi.org/10.1002/0470870834.CH7","url":null,"abstract":"Transplanted human embryonic dopamine neurons reinnervate the striatum in patients with Parkinson's disease. The grafts can exhibit long-term survival without immunological rejection and despite an ongoing disease process and continuous antiparkinsonian drug treatment. Recent findings using positron emission tomography indicate that the grafts are functionally integrated in the patient's brain and release dopamine into the striatum. In the most successful cases, patients have been able to withdraw L-dopa treatment after transplantation and resume an independent life. About two-thirds of grafted patients have shown clinically useful, partial recovery of motor function: increased percentage of time in the 'on'-phase and reduced rigidity and hypokinesia during 'off'-phases, bilaterally but predominantly on the side contralateral to the graft. Gait, speed, balance and dyskinesias have not exhibited any major, consistent improvements. Current research aims at solving three main problems: (a) large amounts of human embryonic mesencephalic tissue are needed for therapeutic effects; (b) symptomatic relief is incomplete and varies between patients; and (c) patient selection and grafting procedure have not been optimized.","PeriodicalId":19323,"journal":{"name":"Novartis Foundation Symposium","volume":"43 3","pages":"110-23; discussion 123-8, 145-7"},"PeriodicalIF":0.0,"publicationDate":"2008-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/0470870834.CH7","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"50786304","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}
Biological fitness is a directly observable quantity with well-known causal components, in contrast to the latent 'g' factor of psychometrics. The study of the causes of variation in fitness should therefore be simpler than the study of variation in mental abilities, but a paucity of data has kept the nature of genetic variation in fitness obscure. We can define an 'f' factor as variation creating positive correlations among components of fitness. There is little doubt that such f factor exist. Perturbations of populations such as mutation or environmental change create such patterns of positive correlation. However, natural selection will tend to minimize variation in any f factor, so it is much less clear whether f causes quantitatively substantial genetic variation within populations. Experimental data are consistent with variation in an f factor within some natural populations. As predicted, f is less important in populations where natural selection has had more opportunity to reshape the correlation matrix. Although one can incorporate variation in g into a study of variation in human fitness, the pace of change in our environment suggests that the results would neither reflect the conditions under which g evolved nor predict future evolutionary changes in g.
{"title":"Is there a g factor for fitness?","authors":"David Houle","doi":"10.1002/0470870850.CH10","DOIUrl":"https://doi.org/10.1002/0470870850.CH10","url":null,"abstract":"Biological fitness is a directly observable quantity with well-known causal components, in contrast to the latent 'g' factor of psychometrics. The study of the causes of variation in fitness should therefore be simpler than the study of variation in mental abilities, but a paucity of data has kept the nature of genetic variation in fitness obscure. We can define an 'f' factor as variation creating positive correlations among components of fitness. There is little doubt that such f factor exist. Perturbations of populations such as mutation or environmental change create such patterns of positive correlation. However, natural selection will tend to minimize variation in any f factor, so it is much less clear whether f causes quantitatively substantial genetic variation within populations. Experimental data are consistent with variation in an f factor within some natural populations. As predicted, f is less important in populations where natural selection has had more opportunity to reshape the correlation matrix. Although one can incorporate variation in g into a study of variation in human fitness, the pace of change in our environment suggests that the results would neither reflect the conditions under which g evolved nor predict future evolutionary changes in g.","PeriodicalId":19323,"journal":{"name":"Novartis Foundation Symposium","volume":"41 5","pages":"149-59; discussion 159-70, 276-80"},"PeriodicalIF":0.0,"publicationDate":"2008-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/0470870850.CH10","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"50786326","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}
IQ gains over time were calculated for each WISC (Wechsler Intelligence Scale for Children) subtest and the subtests ranked by size of gain. Verbal similarities led at 20 points per generation--larger than gains on Raven's Progressive Matrices. Similarities measures on-the-spot problem-solving (something akin to fluid g); verbal subtests that do not measure this show low rates of gain. WISC subtests were also ranked by their correlations with Raven's, the latter being used as a marker for fluid g. The r between the two hierarchies was calculated to approximate a correlation between IQ gains and fluid g. The result of 0.50 contrasts with the negative correlation between IQ gains and the g generated by factor analysing the WISC battery itself, which is generally viewed as predominately a crystallized g. In sum, it appears that human groups can make massive fluid g gains in a period too short to accommodate radical change in the speed and efficiency of neural processes. Moreover, once gains in intelligent behaviour over historical time are seen to be independent of brain physiology, does g really provide a criterion for assessing their significance? Finally, not only a measure of fluid g (which is highly heritable) but also inbreeding depression are shown to be correlated with IQ gains--gains overwhelmingly environmental in origin. Therefore, correlations between such genetically influenced factors and the size of the black/white IQ gap do not show that the gap has a genetic component.
{"title":"IQ gains, WISC subtests and fluid g: g theory and the relevance of Spearman's hypothesis to race.","authors":"J. Flynn","doi":"10.1002/0470870850.CH13","DOIUrl":"https://doi.org/10.1002/0470870850.CH13","url":null,"abstract":"IQ gains over time were calculated for each WISC (Wechsler Intelligence Scale for Children) subtest and the subtests ranked by size of gain. Verbal similarities led at 20 points per generation--larger than gains on Raven's Progressive Matrices. Similarities measures on-the-spot problem-solving (something akin to fluid g); verbal subtests that do not measure this show low rates of gain. WISC subtests were also ranked by their correlations with Raven's, the latter being used as a marker for fluid g. The r between the two hierarchies was calculated to approximate a correlation between IQ gains and fluid g. The result of 0.50 contrasts with the negative correlation between IQ gains and the g generated by factor analysing the WISC battery itself, which is generally viewed as predominately a crystallized g. In sum, it appears that human groups can make massive fluid g gains in a period too short to accommodate radical change in the speed and efficiency of neural processes. Moreover, once gains in intelligent behaviour over historical time are seen to be independent of brain physiology, does g really provide a criterion for assessing their significance? Finally, not only a measure of fluid g (which is highly heritable) but also inbreeding depression are shown to be correlated with IQ gains--gains overwhelmingly environmental in origin. Therefore, correlations between such genetically influenced factors and the size of the black/white IQ gap do not show that the gap has a genetic component.","PeriodicalId":19323,"journal":{"name":"Novartis Foundation Symposium","volume":"39 7","pages":"202-16; discussion 216-27"},"PeriodicalIF":0.0,"publicationDate":"2008-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/0470870850.CH13","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"50786380","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 limited proliferative potential of normal cells in culture, cell replicative senescence, is an accepted model for ageing at the cellular level. Tumour-derived, or viral- or carcinogen-transformed cells have escaped senescence and proliferate without control (immortal). We and others have found that fusion of normal with immortal human cells yields hybrids that have regained growth control and cease division. This demonstrates that the phenotype of replicative senescence is dominant and that cells immortalize because of defects in senescence-related genes. We exploited the recessive nature of immortality and by fusing different immortal cell lines with each other identified four complementation groups for indefinite division. Immortal parental cell lines with similar senescence gene defects when fused yielded hybrids with unlimited division potential and were assigned to the same complementation group. Fusion of immortal cell lines with different gene defects resulted in complementation in the hybrids, which had limited division capability. These parental cell lines were assigned to different complementation groups. Using microcell-mediated chromosome transfer, we then demonstrated that introduction of a normal human chromosome 4 induced senescence only in immortal cell lines assigned to complementation group B. We have now cloned the gene on chromosome 4, MORF4 (mortality factor on chromosome 4). It is a member of a family of seven genes and only MORF4 and the MORF-related genes MRG15 and MRGX are expressed. The predicted protein motifs strongly suggest this is a novel family of transcription factors. We have identified interacting proteins, some of which are also novel. These genes have the potential to modulate expression of a large number of genes by chromatin remodelling. They, therefore, also have the potential to affect tissue function due to changes in expression activity during ageing.
{"title":"Identification of genes involved in cell senescence and immortalization: potential implications for tissue ageing.","authors":"J. Leung, O. Pereira-smith","doi":"10.1002/0470868694.CH10","DOIUrl":"https://doi.org/10.1002/0470868694.CH10","url":null,"abstract":"The limited proliferative potential of normal cells in culture, cell replicative senescence, is an accepted model for ageing at the cellular level. Tumour-derived, or viral- or carcinogen-transformed cells have escaped senescence and proliferate without control (immortal). We and others have found that fusion of normal with immortal human cells yields hybrids that have regained growth control and cease division. This demonstrates that the phenotype of replicative senescence is dominant and that cells immortalize because of defects in senescence-related genes. We exploited the recessive nature of immortality and by fusing different immortal cell lines with each other identified four complementation groups for indefinite division. Immortal parental cell lines with similar senescence gene defects when fused yielded hybrids with unlimited division potential and were assigned to the same complementation group. Fusion of immortal cell lines with different gene defects resulted in complementation in the hybrids, which had limited division capability. These parental cell lines were assigned to different complementation groups. Using microcell-mediated chromosome transfer, we then demonstrated that introduction of a normal human chromosome 4 induced senescence only in immortal cell lines assigned to complementation group B. We have now cloned the gene on chromosome 4, MORF4 (mortality factor on chromosome 4). It is a member of a family of seven genes and only MORF4 and the MORF-related genes MRG15 and MRGX are expressed. The predicted protein motifs strongly suggest this is a novel family of transcription factors. We have identified interacting proteins, some of which are also novel. These genes have the potential to modulate expression of a large number of genes by chromatin remodelling. They, therefore, also have the potential to affect tissue function due to changes in expression activity during ageing.","PeriodicalId":19323,"journal":{"name":"Novartis Foundation Symposium","volume":"34 2","pages":"105-10; discussion 110-5; 146-9"},"PeriodicalIF":0.0,"publicationDate":"2008-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/0470868694.CH10","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"50780412","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 : 2008-10-07DOI: 10.1002/9780470030585.CH12
J. Wolff
Philosophical disagreement about justice rages over at least two questions. The most immediate is a substantial question, concerning the conditions under which particular distributive arrangements can be said to be just or unjust. The second, deeper, question concerns the nature of justice itself. What is justice? Here we can distinguish three views. First, justice as mutual advantage sees justice as essentially a matter of the outcome of a bargain. There are times when two parties can both be better off by making some sort of agreement. Justice, on this view, concerns the distribution of the benefits and burdens of the agreement. Second, justice as reciprocity takes a different approach, looking not at bargaining but at the idea of a fair return or just price, attempting to capture the idea of justice as equal exchange. Finally justice as impartiality sees justice as 'taking the other person's point of view' asking 'how would you like it if it happened to you?' Each model has significantly different consequences for the question of when issues of justice arise and how they should be settled. It is interesting to consider whether any of these models of justice could regulate behaviour between non-human animals.
{"title":"Models of distributive justice.","authors":"J. Wolff","doi":"10.1002/9780470030585.CH12","DOIUrl":"https://doi.org/10.1002/9780470030585.CH12","url":null,"abstract":"Philosophical disagreement about justice rages over at least two questions. The most immediate is a substantial question, concerning the conditions under which particular distributive arrangements can be said to be just or unjust. The second, deeper, question concerns the nature of justice itself. What is justice? Here we can distinguish three views. First, justice as mutual advantage sees justice as essentially a matter of the outcome of a bargain. There are times when two parties can both be better off by making some sort of agreement. Justice, on this view, concerns the distribution of the benefits and burdens of the agreement. Second, justice as reciprocity takes a different approach, looking not at bargaining but at the idea of a fair return or just price, attempting to capture the idea of justice as equal exchange. Finally justice as impartiality sees justice as 'taking the other person's point of view' asking 'how would you like it if it happened to you?' Each model has significantly different consequences for the question of when issues of justice arise and how they should be settled. It is interesting to consider whether any of these models of justice could regulate behaviour between non-human animals.","PeriodicalId":19323,"journal":{"name":"Novartis Foundation Symposium","volume":"278 1","pages":"165-70; discussion 170-80, 216-21"},"PeriodicalIF":0.0,"publicationDate":"2008-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"51133879","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}
Outer hair cells (OHCs) of the mammalian cochlea are equipped with a specific form of cellular motility that is driven by changes of the membrane potential. This electromotility is a membrane-based process generated by the membrane protein prestin (SLC26A5). Current models suggest that prestin undergoes a force-generating conformational transition upon changes of the membrane potential. The voltage dependence of prestin needs to be mediated by a charged particle within the protein, a 'voltage sensor', that can move through the membrane electrical field to trigger these conformational rearrangements. Indeed, voltage sensor translocation can be measured as electrical charge transfer. Here, we review and extend data indicating that charge movement by prestin and consequently electromotility depend on the presence of small monovalent anions such as chloride and bicarbonate at the cytoplasmic side of the membrane. The voltage dependence of prestin varies with concentration and species of the anion present, consistent with a partial translocation of the anion through the membrane. Thus anions may act as extrinsic voltage sensors. These conclusions suggest that charge movement and subsequent conformational rearrangements may relate to anion transport by other SLC26 members. Insights into molecular properties of prestin may provide clues to common mechanisms of anion transport by SLC26 proteins.
{"title":"Interaction of prestin (SLC26A5) with monovalent intracellular anions.","authors":"D. Oliver, Thorsten Schächinger, B. Fakler","doi":"10.1002/0470029579.CH16","DOIUrl":"https://doi.org/10.1002/0470029579.CH16","url":null,"abstract":"Outer hair cells (OHCs) of the mammalian cochlea are equipped with a specific form of cellular motility that is driven by changes of the membrane potential. This electromotility is a membrane-based process generated by the membrane protein prestin (SLC26A5). Current models suggest that prestin undergoes a force-generating conformational transition upon changes of the membrane potential. The voltage dependence of prestin needs to be mediated by a charged particle within the protein, a 'voltage sensor', that can move through the membrane electrical field to trigger these conformational rearrangements. Indeed, voltage sensor translocation can be measured as electrical charge transfer. Here, we review and extend data indicating that charge movement by prestin and consequently electromotility depend on the presence of small monovalent anions such as chloride and bicarbonate at the cytoplasmic side of the membrane. The voltage dependence of prestin varies with concentration and species of the anion present, consistent with a partial translocation of the anion through the membrane. Thus anions may act as extrinsic voltage sensors. These conclusions suggest that charge movement and subsequent conformational rearrangements may relate to anion transport by other SLC26 members. Insights into molecular properties of prestin may provide clues to common mechanisms of anion transport by SLC26 proteins.","PeriodicalId":19323,"journal":{"name":"Novartis Foundation Symposium","volume":"68 ","pages":"244-53; discussion 253-60, 261-4"},"PeriodicalIF":0.0,"publicationDate":"2008-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/0470029579.CH16","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"50753903","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}
Repeated infections with the 'mucosal' pathogen rotavirus are common in children. Subsequent rotavirus infections usually cause milder symptoms than first-time infections. Therefore, although natural rotavirus infection attenuates the severity of subsequent infections, it does not prevent reinfection or mild disease. On the other hand, natural infection with 'systemic' viruses such as measles, mumps, rubella, or varicella often confers life-long protection against mild disease associated with reinfection. The degree to which differences in the pathogenesis of systemic and mucosal pathogens determines differences in the capacity of natural infection to induce life-long protective immunity will be discussed. This paradigm will be used to explore the immunological effector functions associated with protection against rotavirus challenge.
{"title":"Correlates of protection against rotavirus infection and disease.","authors":"P. Offit","doi":"10.1002/0470846534.CH8","DOIUrl":"https://doi.org/10.1002/0470846534.CH8","url":null,"abstract":"Repeated infections with the 'mucosal' pathogen rotavirus are common in children. Subsequent rotavirus infections usually cause milder symptoms than first-time infections. Therefore, although natural rotavirus infection attenuates the severity of subsequent infections, it does not prevent reinfection or mild disease. On the other hand, natural infection with 'systemic' viruses such as measles, mumps, rubella, or varicella often confers life-long protection against mild disease associated with reinfection. The degree to which differences in the pathogenesis of systemic and mucosal pathogens determines differences in the capacity of natural infection to induce life-long protective immunity will be discussed. This paradigm will be used to explore the immunological effector functions associated with protection against rotavirus challenge.","PeriodicalId":19323,"journal":{"name":"Novartis Foundation Symposium","volume":"40 2","pages":"106-13; discussion 114-24"},"PeriodicalIF":0.0,"publicationDate":"2008-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/0470846534.CH8","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"50763972","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}
京公网安备 11010802042870号
京ICP备2023020795号-1
扫码关注我们
求助内容：
应助结果提醒方式：