Pub Date : 2023-01-01DOI: 10.1093/function/zqac065
Adam Pearson, Dominik Haenni, Jamal Bouitbir, Matthew Hunt, Brendan A I Payne, Ashwin Sachdeva, Rachel K Y Hung, Frank A Post, John Connolly, Stellor Nlandu-Khodo, Nevena Jankovic, Milica Bugarski, Andrew M Hall
Nephrotoxicity is a major cause of kidney disease and failure in drug development, but understanding of cellular mechanisms is limited, highlighting the need for better experimental models and methodological approaches. Most nephrotoxins damage the proximal tubule (PT), causing functional impairment of solute reabsorption and systemic metabolic complications. The antiviral drug tenofovir disoproxil fumarate (TDF) is an archetypal nephrotoxin, inducing mitochondrial abnormalities and urinary solute wasting, for reasons that were previously unclear. Here, we developed an automated, high-throughput imaging pipeline to screen the effects of TDF on solute transport and mitochondrial morphology in human-derived RPTEC/TERT1 cells, and leveraged this to generate realistic models of functional toxicity. By applying multiparametric metabolic profiling-including oxygen consumption measurements, metabolomics, and transcriptomics-we elucidated a highly robust molecular fingerprint of TDF exposure. Crucially, we identified that the active metabolite inhibits complex V (ATP synthase), and that TDF treatment causes rapid, dose-dependent loss of complex V activity and expression. Moreover, we found evidence of complex V suppression in kidney biopsies from humans with TDF toxicity. Thus, we demonstrate an effective and convenient experimental approach to screen for disease relevant functional defects in kidney cells in vitro, and reveal a new paradigm for understanding the pathogenesis of a substantial cause of nephrotoxicity.
{"title":"Integration of High-Throughput Imaging and Multiparametric Metabolic Profiling Reveals a Mitochondrial Mechanism of Tenofovir Toxicity.","authors":"Adam Pearson, Dominik Haenni, Jamal Bouitbir, Matthew Hunt, Brendan A I Payne, Ashwin Sachdeva, Rachel K Y Hung, Frank A Post, John Connolly, Stellor Nlandu-Khodo, Nevena Jankovic, Milica Bugarski, Andrew M Hall","doi":"10.1093/function/zqac065","DOIUrl":"https://doi.org/10.1093/function/zqac065","url":null,"abstract":"<p><p>Nephrotoxicity is a major cause of kidney disease and failure in drug development, but understanding of cellular mechanisms is limited, highlighting the need for better experimental models and methodological approaches. Most nephrotoxins damage the proximal tubule (PT), causing functional impairment of solute reabsorption and systemic metabolic complications. The antiviral drug tenofovir disoproxil fumarate (TDF) is an archetypal nephrotoxin, inducing mitochondrial abnormalities and urinary solute wasting, for reasons that were previously unclear. Here, we developed an automated, high-throughput imaging pipeline to screen the effects of TDF on solute transport and mitochondrial morphology in human-derived RPTEC/TERT1 cells, and leveraged this to generate realistic models of functional toxicity. By applying multiparametric metabolic profiling-including oxygen consumption measurements, metabolomics, and transcriptomics-we elucidated a highly robust molecular fingerprint of TDF exposure. Crucially, we identified that the active metabolite inhibits complex V (ATP synthase), and that TDF treatment causes rapid, dose-dependent loss of complex V activity and expression. Moreover, we found evidence of complex V suppression in kidney biopsies from humans with TDF toxicity. Thus, we demonstrate an effective and convenient experimental approach to screen for disease relevant functional defects in kidney cells in vitro, and reveal a new paradigm for understanding the pathogenesis of a substantial cause of nephrotoxicity.</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9840465/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9444607","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-01-01DOI: 10.1093/function/zqac070
Birgit Hoeger, Susanna Zierler
Ions are indispensable for cellular integrity. They constitute organellar identity and homeostasis within the physical barrier of biomembranes, support electrical potential across membranes, provide nutritional support, and serve as signaling entities that are able to adapt to varying challenges within milliseconds. Ion channels are the molecular mediators that shuttle ions between the different cellular compartments, often rather unspecific for certain cations or anions, often in a surprisingly selective manner. Their critical role in every cell type is undoubted. Immune cells are specialized cell types with unique molecular properties. They need to be able to rapidly adapt to various kinds of sudden environmental changes, and, to defend the body from dangerous intruders, consequently respond by massive cellular rearrangements in terms of activation, differentiation, or function. These require pronounced molecular rearrangements, among which ions and ion channels take a central part. Within the last two decades, a number of excellent studies have shed light on the role of distinct ion channels and transporters in immunity. Foremost, the identification of the molecular components ORAI and STIM that mediate store-operated calcium signals in activating lymphocytic and innate immune cells has significantly pushed the field toward studying ion movements and their regulation as the basis for understanding immunity.1–3 With the identification of detrimental mutations in ORAIand STIM-encoding genes causing human immunodeficiencies due to lack of appropriate calcium entry machineries,4 the stage was set for a comprehensive investigation of ion channels in health and disease. Since then, we have gained considerable insight into certain ion channel families and mechanisms. Much attention has been attributed to understanding ion homeostasis and ion signaling in T-cell immunity. Very recently, the attention has moved to VGCCs (voltage-gated Ca2+ channel subunits) being relevant in calcium signaling and triggering downstream effector functions in T cells, without functioning as ion channels themselves.5 To date, a growing number of ion-conducting channels and transporters have been identified to modulate T-, B-, NK, and dendritic cell function, monocytes, macrophages, and neutrophils, as well as mast cell homeostasis (Figure 1).3 This is impressive, but we are still far away from understanding the complex relationships of ion conductance and cellular responses, notwithstanding their contribution to (human) diseases. So where do we go from here? In our opinion, there are a few critical questions that will guide our immediate and longterm attention, and require joint efforts to be deciphered. First, it is still partly unclear which ion channels and family members are functionally expressed in diverse immune cell subsets, which proteins they colocalize or interact with, and under which preconditions they are active. We will surely untangle yet unrecognized ion c
{"title":"Ion Channels and Transporters in Immunity-Where do We Stand?","authors":"Birgit Hoeger, Susanna Zierler","doi":"10.1093/function/zqac070","DOIUrl":"https://doi.org/10.1093/function/zqac070","url":null,"abstract":"Ions are indispensable for cellular integrity. They constitute organellar identity and homeostasis within the physical barrier of biomembranes, support electrical potential across membranes, provide nutritional support, and serve as signaling entities that are able to adapt to varying challenges within milliseconds. Ion channels are the molecular mediators that shuttle ions between the different cellular compartments, often rather unspecific for certain cations or anions, often in a surprisingly selective manner. Their critical role in every cell type is undoubted. Immune cells are specialized cell types with unique molecular properties. They need to be able to rapidly adapt to various kinds of sudden environmental changes, and, to defend the body from dangerous intruders, consequently respond by massive cellular rearrangements in terms of activation, differentiation, or function. These require pronounced molecular rearrangements, among which ions and ion channels take a central part. Within the last two decades, a number of excellent studies have shed light on the role of distinct ion channels and transporters in immunity. Foremost, the identification of the molecular components ORAI and STIM that mediate store-operated calcium signals in activating lymphocytic and innate immune cells has significantly pushed the field toward studying ion movements and their regulation as the basis for understanding immunity.1–3 With the identification of detrimental mutations in ORAIand STIM-encoding genes causing human immunodeficiencies due to lack of appropriate calcium entry machineries,4 the stage was set for a comprehensive investigation of ion channels in health and disease. Since then, we have gained considerable insight into certain ion channel families and mechanisms. Much attention has been attributed to understanding ion homeostasis and ion signaling in T-cell immunity. Very recently, the attention has moved to VGCCs (voltage-gated Ca2+ channel subunits) being relevant in calcium signaling and triggering downstream effector functions in T cells, without functioning as ion channels themselves.5 To date, a growing number of ion-conducting channels and transporters have been identified to modulate T-, B-, NK, and dendritic cell function, monocytes, macrophages, and neutrophils, as well as mast cell homeostasis (Figure 1).3 This is impressive, but we are still far away from understanding the complex relationships of ion conductance and cellular responses, notwithstanding their contribution to (human) diseases. So where do we go from here? In our opinion, there are a few critical questions that will guide our immediate and longterm attention, and require joint efforts to be deciphered. First, it is still partly unclear which ion channels and family members are functionally expressed in diverse immune cell subsets, which proteins they colocalize or interact with, and under which preconditions they are active. We will surely untangle yet unrecognized ion c","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/93/e3/zqac070.PMC9846422.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9133762","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-01-01DOI: 10.1093/function/zqac073
Anant B Parekh, Lord Bhikhu C Parekh
{"title":"\"Study the Past if You Would Define the Future.\"-Confucius.","authors":"Anant B Parekh, Lord Bhikhu C Parekh","doi":"10.1093/function/zqac073","DOIUrl":"https://doi.org/10.1093/function/zqac073","url":null,"abstract":"","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9850269/pdf/zqac073.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9133763","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-01-01DOI: 10.1093/function/zqac055
Sonia Sebastian, Lee S Weinstein, Andreas Ludwig, Patricia Munroe, Andrew Tinker
We aimed to determine the pathophysiological impact of heart rate (HR) slowing on cardiac function. We have recently developed a murine model in which it is possible to conditionally delete the stimulatory heterotrimeric G-protein (Gαs) in the sinoatrial (SA) node after the addition of tamoxifen using cre-loxP technology. The addition of tamoxifen leads to bradycardia. We used this approach to examine the physiological and pathophysiological effects of HR slowing. We first looked at the impact on exercise performance by running the mice on a treadmill. After the addition of tamoxifen, mice with conditional deletion of Gαs in the SA node ran a shorter distance at a slower speed. Littermate controls preserved their exercise capacity after tamoxifen. Results consistent with impaired cardiac capacity in the mutants were also obtained with a dobutamine echocardiographic stress test. We then examined if HR reduction influenced pathological cardiac hypertrophy using two models: ligation of the left anterior descending coronary artery for myocardial infarction and abdominal aortic banding for hypertensive heart disease. In littermate controls, both procedures resulted in cardiac hypertrophy. However, induction of HR reduction prior to surgical intervention significantly ameliorated the hypertrophy. In order to assess potential protein kinase pathways that may be activated in the left ventricle by relative bradycardia, we used a phospho-antibody array and this revealed selective activation of phosphoinositide-3 kinase. In conclusion, HR reduction protects against pathological cardiac hypertrophy but limits physiological exercise capacity.
{"title":"Slowing Heart Rate Protects Against Pathological Cardiac Hypertrophy.","authors":"Sonia Sebastian, Lee S Weinstein, Andreas Ludwig, Patricia Munroe, Andrew Tinker","doi":"10.1093/function/zqac055","DOIUrl":"https://doi.org/10.1093/function/zqac055","url":null,"abstract":"<p><p>We aimed to determine the pathophysiological impact of heart rate (HR) slowing on cardiac function. We have recently developed a murine model in which it is possible to conditionally delete the stimulatory heterotrimeric G-protein (Gα<sub>s</sub>) in the sinoatrial (SA) node after the addition of tamoxifen using cre-loxP technology. The addition of tamoxifen leads to bradycardia. We used this approach to examine the physiological and pathophysiological effects of HR slowing. We first looked at the impact on exercise performance by running the mice on a treadmill. After the addition of tamoxifen, mice with conditional deletion of Gα<sub>s</sub> in the SA node ran a shorter distance at a slower speed. Littermate controls preserved their exercise capacity after tamoxifen. Results consistent with impaired cardiac capacity in the mutants were also obtained with a dobutamine echocardiographic stress test. We then examined if HR reduction influenced pathological cardiac hypertrophy using two models: ligation of the left anterior descending coronary artery for myocardial infarction and abdominal aortic banding for hypertensive heart disease. In littermate controls, both procedures resulted in cardiac hypertrophy. However, induction of HR reduction prior to surgical intervention significantly ameliorated the hypertrophy. In order to assess potential protein kinase pathways that may be activated in the left ventricle by relative bradycardia, we used a phospho-antibody array and this revealed selective activation of phosphoinositide-3 kinase. In conclusion, HR reduction protects against pathological cardiac hypertrophy but limits physiological exercise capacity.</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9761894/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10750916","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-01-01DOI: 10.1093/function/zqac067
Nils Helge Schebb, Dieter Steinhilber
The concept of specialized proresolving lipid mediators (SPMs) is such a perfect model: Different enzymes of the arachidonic acid cascade lead to formation of specific multiply hydroxylated PUFAs. These SPM stop inflammation at high potency through the binding to G-protein-coupled receptors (GPCRs). 1 A year ago we showed, based on own data and current lit-erature, that neither the formation routes of trihydroxylated specialized proresolving lipid mediators such as lipoxins and resolvins via lipoxygenases are convincing nor the signaling through particular GPCRs has been conclusively demonstrated. 2 This challenges the biological role of these SPMs. However, most attention focused on the finding that analytical methods to demonstrate their formation and occurrence in biological samples are inappropriate, while methods validated accord-ing to internationally agreed standards largely fail to detect the molecules. 2 − 4 Although this started an intense discussion, our questions regarding the formation route, the signaling, and the validity of detection methods have not yet been addressed. Meanwhile, many SPM papers, which show “illustrations” of LC–MS chro-matograms instead of original data are marked in PubPeer but theauthorsareyettoprovideoriginaldatatoprovetheexistence of SPMs in their samples. Instead, arguments such as the testing of SPM in clinical trials, the own h -index or the number of SPM
{"title":"What Mediates the Inflammation Resolution?","authors":"Nils Helge Schebb, Dieter Steinhilber","doi":"10.1093/function/zqac067","DOIUrl":"https://doi.org/10.1093/function/zqac067","url":null,"abstract":"The concept of specialized proresolving lipid mediators (SPMs) is such a perfect model: Different enzymes of the arachidonic acid cascade lead to formation of specific multiply hydroxylated PUFAs. These SPM stop inflammation at high potency through the binding to G-protein-coupled receptors (GPCRs). 1 A year ago we showed, based on own data and current lit-erature, that neither the formation routes of trihydroxylated specialized proresolving lipid mediators such as lipoxins and resolvins via lipoxygenases are convincing nor the signaling through particular GPCRs has been conclusively demonstrated. 2 This challenges the biological role of these SPMs. However, most attention focused on the finding that analytical methods to demonstrate their formation and occurrence in biological samples are inappropriate, while methods validated accord-ing to internationally agreed standards largely fail to detect the molecules. 2 − 4 Although this started an intense discussion, our questions regarding the formation route, the signaling, and the validity of detection methods have not yet been addressed. Meanwhile, many SPM papers, which show “illustrations” of LC–MS chro-matograms instead of original data are marked in PubPeer but theauthorsareyettoprovideoriginaldatatoprovetheexistence of SPMs in their samples. Instead, arguments such as the testing of SPM in clinical trials, the own h -index or the number of SPM","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/9a/85/zqac067.PMC9825276.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10303937","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-01-01DOI: 10.1093/function/zqad014
R A North
Once upon a time, scientists wrote with quills, then pens, then typewriters. There was often someone else well trained in the art, often poorly paid, who sat behind the typewriter, working from a yellow paper legal pad, or even from a simple tape recorder. That was the time when one went to the library in person, when copying machines were not available or very expensive, and when one made notes about another paper on an index card, which fitted into a metal box, where it sometimes remained for a long time without being viewed again. It was in that period when I received, in the mail, a request to review a manuscript from the journal Life Sciences. The year before, Marcello Tonini and I had published a paper in the British Journal of Pharmacology,1 which described the hyperpolarizing action of morphine on neurons of the myenteric plexus. This is Auerbach’s plexus, one of the two major ganglionated nerve plexuses in the wall of the intestine: A few years before, working with Syogoro Nishi in Chicago, I had reported the first intracellular recordings from these neurons.2 A short segment of guinea pig ileum had been widely used over the years as an in vitro bioassay for morphine and related compounds: Electrical stimulation of the myenteric neurons caused the release of acetylcholine, which contracted the longitudinal muscle, and this contraction could be readily recorded on a kymograph (smoked drum) or, later, a pen recorder. By studying a wide variety of morphine-like compounds, agonists and antagonists, it had been concluded that the receptor on the myenteric neurons was extremely similar to the receptor through which morphine evinced its analgesic and other effects in man.3 The bioassay had been a key component of the recent identification of the first endogenous opioids, the pentapeptides metand leu-enkephalin.4 The manuscript that came for my review from Life Sciences described the hyperpolarizing action of enkephalins of myenteric neurons, studied by intracellular microelectrode recording. It began:
{"title":"Plagiarism Reimagined.","authors":"R A North","doi":"10.1093/function/zqad014","DOIUrl":"https://doi.org/10.1093/function/zqad014","url":null,"abstract":"Once upon a time, scientists wrote with quills, then pens, then typewriters. There was often someone else well trained in the art, often poorly paid, who sat behind the typewriter, working from a yellow paper legal pad, or even from a simple tape recorder. That was the time when one went to the library in person, when copying machines were not available or very expensive, and when one made notes about another paper on an index card, which fitted into a metal box, where it sometimes remained for a long time without being viewed again. It was in that period when I received, in the mail, a request to review a manuscript from the journal Life Sciences. The year before, Marcello Tonini and I had published a paper in the British Journal of Pharmacology,1 which described the hyperpolarizing action of morphine on neurons of the myenteric plexus. This is Auerbach’s plexus, one of the two major ganglionated nerve plexuses in the wall of the intestine: A few years before, working with Syogoro Nishi in Chicago, I had reported the first intracellular recordings from these neurons.2 A short segment of guinea pig ileum had been widely used over the years as an in vitro bioassay for morphine and related compounds: Electrical stimulation of the myenteric neurons caused the release of acetylcholine, which contracted the longitudinal muscle, and this contraction could be readily recorded on a kymograph (smoked drum) or, later, a pen recorder. By studying a wide variety of morphine-like compounds, agonists and antagonists, it had been concluded that the receptor on the myenteric neurons was extremely similar to the receptor through which morphine evinced its analgesic and other effects in man.3 The bioassay had been a key component of the recent identification of the first endogenous opioids, the pentapeptides metand leu-enkephalin.4 The manuscript that came for my review from Life Sciences described the hyperpolarizing action of enkephalins of myenteric neurons, studied by intracellular microelectrode recording. It began:","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10165543/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9479235","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-01-01DOI: 10.1093/function/zqad006
Normand Leblanc
The control of air flow resistance in the airways during breathing cycles is governed by a fine balance between the parasympathetic and sympathetic branches of the autonomic nervous system targeting airway smooth muscle cells.1,2 During eupnea, airway smooth muscle exhibits basal tone that is controlled by postganglionic input from parasympathetic cholinergic and noncholinergic nerves and sympathetic adrenergic nerves. This basal airway smooth muscle tone is primarily driven by parasympathetic cholinergic nerves, and is opposed in most species by sympathetic nerve fibers that promote relaxation through β-adrenergic receptor signaling. There is also evidence for the involvement of parasympathetic noncholinergic postganglionic nerves, which mediate a relaxation on a slower time course than the cholinergic contraction and appear to be primarily involved in reflexively countering bronchospastic activity of the airways triggered by an insult such as coughing or exposure to a noxious substance. Autonomic regulation of basal tone during eupnea is profoundly regulated by bronchopulmonary as well as extrapulmonary afferent nerve fibers that reflexively enhance or attenuate airway smooth muscle tone by opposing or relieving postganglionic cholinergic contraction. Although the distribution and function of parasympathetic cholinergic nerve fibers responsible for maintaining airway smooth muscle tone is widespread across species, sympathetic and noncholinergic innervation of the airways is not a common denominator and varies widely in different species. For example, sympathetic adrenergic innervation is poorly developed in human airways, but is prominent in dogs where it promotes relaxation. Mice and rats are devoid of any kind of relaxant innervation. Nevertheless, both αand β-adrenergic receptors are expressed in human airways and can modulate smooth muscle tone when stimulated by circulating or locally released autacoids. Dysfunction of the autonomic nervous system is a major contributor to the enhanced bronchospastic activity of the airways in chronic obstructive pulmonary disease (COPD) and asthma, and blocking cholinergic muscarinic receptors and/or stimulating β-adrenergic receptors have proven efficacious in alleviating bronchospastic activity.3,4 Airway smooth muscle cells express both the M2 and M3 subclasses of muscarinic receptors targeted by the neurotransmitter acetylcholine (ACh).5 The dogmatic view has been that the bronchoconstriction mediated by parasympathetic cholinergic stimulation mainly involves activation of the M3 receptor subtype, while the M2 receptor antagonizes the relaxation caused by β-adrenergic receptors but produces little direct contractile effect on airway smooth muscle. In contrast to the dogma, a study by Struckmann et al.6 using M2, M3, or double M2/M3 receptor knockout (KO) mice showed that both receptor subtypes were required to produce the maximal bronchoconstriction elicited by ACh, albeit the M3 receptor produced gr
{"title":"β-Adrenergic Receptor Antagonism of Cholinergic Stimulation of Airway Smooth Muscle Contraction: An Old Receptor Requires a Fresh Look.","authors":"Normand Leblanc","doi":"10.1093/function/zqad006","DOIUrl":"https://doi.org/10.1093/function/zqad006","url":null,"abstract":"The control of air flow resistance in the airways during breathing cycles is governed by a fine balance between the parasympathetic and sympathetic branches of the autonomic nervous system targeting airway smooth muscle cells.1,2 During eupnea, airway smooth muscle exhibits basal tone that is controlled by postganglionic input from parasympathetic cholinergic and noncholinergic nerves and sympathetic adrenergic nerves. This basal airway smooth muscle tone is primarily driven by parasympathetic cholinergic nerves, and is opposed in most species by sympathetic nerve fibers that promote relaxation through β-adrenergic receptor signaling. There is also evidence for the involvement of parasympathetic noncholinergic postganglionic nerves, which mediate a relaxation on a slower time course than the cholinergic contraction and appear to be primarily involved in reflexively countering bronchospastic activity of the airways triggered by an insult such as coughing or exposure to a noxious substance. Autonomic regulation of basal tone during eupnea is profoundly regulated by bronchopulmonary as well as extrapulmonary afferent nerve fibers that reflexively enhance or attenuate airway smooth muscle tone by opposing or relieving postganglionic cholinergic contraction. Although the distribution and function of parasympathetic cholinergic nerve fibers responsible for maintaining airway smooth muscle tone is widespread across species, sympathetic and noncholinergic innervation of the airways is not a common denominator and varies widely in different species. For example, sympathetic adrenergic innervation is poorly developed in human airways, but is prominent in dogs where it promotes relaxation. Mice and rats are devoid of any kind of relaxant innervation. Nevertheless, both αand β-adrenergic receptors are expressed in human airways and can modulate smooth muscle tone when stimulated by circulating or locally released autacoids. Dysfunction of the autonomic nervous system is a major contributor to the enhanced bronchospastic activity of the airways in chronic obstructive pulmonary disease (COPD) and asthma, and blocking cholinergic muscarinic receptors and/or stimulating β-adrenergic receptors have proven efficacious in alleviating bronchospastic activity.3,4 Airway smooth muscle cells express both the M2 and M3 subclasses of muscarinic receptors targeted by the neurotransmitter acetylcholine (ACh).5 The dogmatic view has been that the bronchoconstriction mediated by parasympathetic cholinergic stimulation mainly involves activation of the M3 receptor subtype, while the M2 receptor antagonizes the relaxation caused by β-adrenergic receptors but produces little direct contractile effect on airway smooth muscle. In contrast to the dogma, a study by Struckmann et al.6 using M2, M3, or double M2/M3 receptor knockout (KO) mice showed that both receptor subtypes were required to produce the maximal bronchoconstriction elicited by ACh, albeit the M3 receptor produced gr","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/b0/fa/zqad006.PMC9972342.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9115351","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-01-01DOI: 10.1093/function/zqad037
Shaomin Li
essi v el y impairs cogniti v e function,
{"title":"Soluble Aβ Oligomers Formed Channels Leading to Calcium Dysregulation.","authors":"Shaomin Li","doi":"10.1093/function/zqad037","DOIUrl":"https://doi.org/10.1093/function/zqad037","url":null,"abstract":"essi v el y impairs cogniti v e function,","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10423025/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10006229","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-01-01DOI: 10.1093/function/zqad005
Ole H Petersen
{"title":"Physiology and Pathophysiology 2023.","authors":"Ole H Petersen","doi":"10.1093/function/zqad005","DOIUrl":"https://doi.org/10.1093/function/zqad005","url":null,"abstract":"","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9912100/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10737772","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-01-01DOI: 10.1093/function/zqac071
Valerie B O'Donnell
Ple a s e no t e: Ch a n g e s m a d e a s a r e s ul t of p u blishing p roc e s s e s s uc h a s copy-e di ting, for m a t ting a n d p a g e n u m b e r s m ay no t b e r eflec t e d in t his ve r sion. For t h e d efini tive ve r sion of t his p u blica tion, ple a s e r ef e r to t h e p u blish e d sou rc e. You a r e a dvise d to cons ul t t h e p u blish e r’s ve r sion if you wish to ci t e t his p a p er.
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