Journal of Physiology-London最新文献

{"title":"Response to - Exposing mice to extremely hypertonic treatments: A recurring problem in lactate research.","authors":"Seth F McCarthy, Isabel Moberg, Sarah Bellaflor, Michael S Finch, Tom J Hazell, Rebecca E K MacPherson","doi":"10.1113/JP287909","DOIUrl":"https://doi.org/10.1113/JP287909","url":null,"abstract":"","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2024-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142755807","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rad-mediated inhibition of CaV1.2 channel activity contributes to uterine artery haemodynamic adaptation to pregnancy","authors":"Xiang-Qun Hu,&nbsp;Rui Song,&nbsp;Chiranjib Dasgupta,&nbsp;Taiming Liu,&nbsp;Meijuan Zhang,&nbsp;Stephen Twum-Barimah,&nbsp;Arlin B. Blood,&nbsp;Lubo Zhang","doi":"10.1113/JP287334","DOIUrl":"10.1113/JP287334","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 \u0000 <div>The striking increase of uterine blood flow during pregnancy is essential for normal fetal development as well as for cardiovascular well-being of the mother. Yet, the underlying mechanisms of pregnancy-mediated vasodilatation of the uterine artery are not fully understood. In this study, we test the hypothesis that Rad, a monomeric G protein, is a novel regulatory mechanism in inhibiting Ca_V1.2 channel currents in uterine artery haemodynamic adaptation to pregnancy in a sheep model. We found that pregnancy significantly upregulates Rad expression and decreases Ca_V1.2 channel currents in uterine arterial smooth muscle cells. <i>Rad</i> knockdown <i>ex vivo</i> and <i>in vivo</i> increases Ca_V1.2 activity and channel window currents by reducing steady-state inactivation in uterine arteries of pregnant sheep, recapitulating the phenotype of uterine arteries in non-pregnant animals. Moreover, <i>Rad</i> knockdown <i>in vivo</i> in pregnant sheep enhances myogenic tone and phenylephrine-induced vasoconstriction of uterine arteries. Whereas knockdown of <i>Rad</i> has no effect on mesenteric arterial Ca_V1.2 channel activity and mean arterial blood pressure, it significantly increases uterine vascular resistance and decreases uterine artery blood flow. Our study reveals a novel cause-and-effect mechanism of Rad in pregnancy-induced suppression of Ca_V1.2 channel activity in uterine arteries to facilitate increased uterine blood flow, providing new insights into fundamental mechanisms of uterine haemodynamic adaptation to pregnancy.\u0000\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure>\u0000 </div>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key points</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>Pregnancy suppresses Ca_V1.2 channel currents in uterine arterial smooth muscle cells.</li>\u0000 \u0000 <li>Rad, a monomeric G protein, is upregulated in uterine arteries of pregnant sheep.</li>\u0000 \u0000 <li><i>Rad</i> knockdown <i>ex vivo</i> or <i>in vivo</i> increases Ca_V1.2 channel currents in uterine arteries from pregnant ewes.</li>\u0000 \u0000 <li><i>In vivo</i> knockdown of <i>Rad</i> elevates uterine vascular resistance and decreases uterine blood flow in pregnant sheep.</li>\u0000 \u0000 <li>The study reveals a novel mechanism of Rad in pregnancy-induced suppression of Ca_V1.2 channel activity in uterine arterial haemodynamic adaptation to pregnancy.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":"602 24","pages":"6729-6744"},"PeriodicalIF":4.7,"publicationDate":"2024-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142755805","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ultrastructure and cardiac impulse propagation: scaling up from microscopic to macroscopic conduction.","authors":"Zhilin Qu, Peter Hanna, Olujimi A Ajijola, Alan Garfinkel, Kalyanam Shivkumar","doi":"10.1113/JP287632","DOIUrl":"https://doi.org/10.1113/JP287632","url":null,"abstract":"<p><p>The standard conception of cardiac conduction is based on the cable theory of nerve conduction, which treats cardiac tissue as a continuous syncytium described by the Hodgkin-Huxley equations. However, cardiac tissue is composed of discretized cells with microscopic and macroscopic heterogeneities and discontinuities, such as subcellular localizations of sodium channels and connexins. In addition to this, there are heterogeneities in the distribution of sympathetic and parasympathetic nerves, which powerfully regulate impulse propagation. In the continuous models, the ultrastructural details, i.e. the microscopic heterogeneities and discontinuities, are ignored by 'coarse graining' or 'smoothing'. However, these ultrastructural components may play crucial roles in cardiac conduction and arrhythmogenesis, particularly in disease states. We discuss the current progress of modelling the effects of ultrastructural components on electrical conduction, the issues and challenges faced by the cardiac modelling community, and how to scale up conduction properties at the subcellular (microscopic) scale to the tissue and whole-heart (macroscopic) scale in future modelling and experimental studies, i.e. how to link the ultrastructure at different scales to impulse conduction and arrhythmogenesis in the heart.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2024-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142755810","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Muscular strength, endothelial function and cognitive disorders: state of the art.","authors":"Yuri Sanchez-Martinez, Jose P Lopez-Lopez, Isabela Gomez-Montoya, Daniela Hernandez-Quiñones, Gabriela Ruiz-Uribe, Zully Rincón-Rueda, Ronald G Garcia, Patricio Lopez-Jaramillo","doi":"10.1113/JP285939","DOIUrl":"https://doi.org/10.1113/JP285939","url":null,"abstract":"<p><p>In recent years, the ageing population has increasingly grown. This process carries a range of pathophysiological changes involving alterations in the skeletal muscle, vascular endothelium and brain function, becoming an important risk factor for developing cognitive disorders and cardiovascular diseases. With ageing, there is a decrease in muscle mass and muscle strength, and a relationship between muscle strength decrease and cognitive decline has been shown. Lower handgrip strength has been linked to memory impairment, lower global cognitive function, decreased attention and reduced visuospatial abilities in the elderly, but understanding of the underlying mechanisms that explain the link between altered skeletal muscle function and structure, endothelial dysfunction, and the role of endothelial dysfunction in the onset of cognitive disorders has been scarcely explored. This review aims to detail the cellular and molecular mechanisms by which the progressive changes associated with ageing can alter healthy skeletal muscle and endothelial function, creating an environment of oxidative stress, inflammation and mitochondrial dysfunction. These changes can lead to reduced muscle strength, and the secretion of detrimental endothelial factors, resulting in endothelial dysfunction, blood-brain barrier disruption, and damage to neurons and microglia, ultimately accelerating the onset of cognitive disorders in the elderly. In addition, we aimed to describe the mechanisms that potentially explain how preserving muscular function with resistance training could prevent brain function deterioration, including the production of different factors that allow an improved endothelial function, haemodynamic parameters and brain plasticity, ultimately delaying the onset of cognitive impairment and chronic diseases.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2024-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142755802","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neural control of the heart: intrinsic cardiac ganglion neurons.","authors":"David J Adams","doi":"10.1113/JP287894","DOIUrl":"https://doi.org/10.1113/JP287894","url":null,"abstract":"","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2024-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142752109","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The gating properties of Drosophila NMJ glutamate receptors and their dependence on Neto","authors":"Tae Hee Han,&nbsp;Rosario Vicidomini,&nbsp;Cathy Isaura Ramos,&nbsp;Mark L. Mayer,&nbsp;Mihaela Serpe","doi":"10.1113/JP287331","DOIUrl":"10.1113/JP287331","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 \u0000 <div>The <i>Drosophila</i> neuromuscular junction (NMJ) is a powerful genetic system that has revealed numerous conserved mechanisms for synapse development and homeostasis. The fly NMJ uses glutamate as the excitatory neurotransmitter and relies on kainate-type glutamate receptors and their auxiliary protein Neto for synapse assembly and function. However, despite decades of study, the reconstitution of NMJ glutamate receptors using heterologous systems has been achieved only recently, and there are no reports on the gating properties for the recombinant receptors. Here, using outside-out, patch clamp recordings and fast ligand application, we examine for the first time the biophysical properties of native type-A and type-B NMJ receptors in complexes with either Neto-α or Neto-β and compare them with recombinant receptors expressed in HEK293T cells. We found that type-A and type-B receptors have strikingly different gating properties that are further modulated by Neto-α and Neto-β. We captured single-channel events and revealed major differences between type-A and type-B receptors and also between Neto splice variants. Surprisingly, we found that deactivation is extremely fast and that the decay of synaptic currents resembles the rate of ionotropic glutamate receptor (iGluR) desensitization. The functional analyses of recombinant iGluRs that we report here should greatly facilitate the interpretation of compound <i>in vivo</i> phenotypes of mutant animals.\u0000\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure>\u0000 </div>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key points</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>We report the reconstitution of <i>Drosophila</i> neuromuscular junction ionotropic glutamate receptors (iGluRs) with Neto splice forms.</li>\u0000 \u0000 <li>Using outside-out patches and fast ligand application, we examine the deactivation and desensitization of the four iGluR/Neto complexes found <i>in vivo</i>.</li>\u0000 \u0000 <li>Expression of functional channels is absolutely dependent on Neto.</li>\u0000 \u0000 <li>Single-channel recordings revealed different lifetimes for different receptor complexes.</li>\u0000 \u0000 <li>The decay of synaptic currents is controlled by desensitization.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":"602 24","pages":"7043-7064"},"PeriodicalIF":4.7,"publicationDate":"2024-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1113/JP287331","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142733635","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Context-dependent orientation discontinuity encoding by gamma rhythms in mouse primary visual cortex","authors":"Baitao Liao,&nbsp;Qiang Gong,&nbsp;Xiaxin Sun,&nbsp;Haolun Liu,&nbsp;Haoran Deng,&nbsp;Yan Cui,&nbsp;Shuang Yu,&nbsp;Xiaotong Yang,&nbsp;Daqing Guo,&nbsp;Yang Xia,&nbsp;Dezhong Yao,&nbsp;Ke Chen","doi":"10.1113/JP286936","DOIUrl":"10.1113/JP286936","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 \u0000 <div>Through the modulation of its surround, an identical visual stimulus can be perceived as more or less salient, allowing it to either stand out or seamlessly integrate with the rest of the visual scene. Gamma rhythms are associated with processing stimulus features across extensive areas of the visual field. Consistent with this concept, the magnitude of visually induced gamma rhythm depends on how well stimulus features aligned both within and outside the classical receptive field (CRF) at the recording site. However, there still exists some uncertainty regarding the encoding of context-modulated orientation discontinuity by gamma rhythms. To address this concern, we conducted extracellular recordings in layers II/III and IV of area V1 using lightly anaesthetized mice to investigate the gamma tuning for stimuli with orientation discontinuity. Our study revealed that gamma rhythms exhibit a preference for stimuli with orientation discontinuity similar to the spiking responses observed in V1, which contradicts the findings of previous studies. Furthermore, the gamma tuning of discontinuous orientations exhibits a moderate correlation with spike tuning and a positive correlation with the strength of surround suppression. Therefore, our study suggests a close association between gamma tuning and nearby spiking tuning; additionally, it highlights the connection between the encoding of visual features by gamma rhythms and functional architecture, as well as neural signal integration.\u0000\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure>\u0000 </div>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key points</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>Visual context modulates the gamma rhythms in the primary visual cortex.</li>\u0000 \u0000 <li>Discontinuous orientation elicits significantly enhanced gamma rhythms compared to the iso-orientation stimulus.</li>\u0000 \u0000 <li>The gamma tuning of discontinuous orientations exhibits a moderate correlation with spike tuning.</li>\u0000 \u0000 <li>Gamma tuning of orientation discontinuity exhibits a positive correlation with the strength of surround suppression.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":"602 24","pages":"6959-6972"},"PeriodicalIF":4.7,"publicationDate":"2024-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142711581","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Incretin impact on gastric function in obesity: physiology, and pharmacological, surgical and endoscopic treatments.","authors":"Michael Camilleri","doi":"10.1113/JP287535","DOIUrl":"https://doi.org/10.1113/JP287535","url":null,"abstract":"<p><p>The aims of this review are to appraise the role of the stomach in satiation, the effects of incretin and other hormone agonists on weight loss and the role of altered gastric functions in their effects on obesity or glycaemic control. In addition to the gut in its role in enzymatic digestion and hormonal responses to nutrient ingestion, gastric motor functions include accommodation, trituration and emptying [gastric emptying (GE)] of food and elicitation of postprandial satiation and satiety. The postprandially released hormones most extensively studied and utilized therapeutically are glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP). Their mechanisms of action include stimulation of pancreatic β cells to produce insulin. However, GLP-1 reduces glucagon and slows GE, whereas GIP increases glucagon and does not alter GE. Molecular modifications of GLP-1 (which has a T_1/2 of 3 min) led to the development of long-acting subcutaneous or oral pharmacological agents that have been approved for the treatment of obesity, and their effects on gastric function are documented. Other medications in development target other molecular mechanisms, including glucagon and amylin. Small-molecule GLP-1 receptor agonists are promising for the treatment of obesity and may also slow GE. Bariatric surgery and endoscopy increase satiation by restricting gastric size; in addition Roux-en-Y gastric bypass and to a lesser extent sleeve gastrectomy (but not endoscopic gastroplasty) increase postprandial circulating incretins, reducing appetite. In conclusion the stomach's function is integral to the impact of the most effective pharmacological and procedural reversal of obesity related to the incretin revolution.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2024-11-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142711599","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Food for thought: implications of exercise-induced changes to cerebral glucose metabolism in ageing and Alzheimer's disease.","authors":"Stuart P S Mladen, Jack Bone, John R M Renwick, Aedan J Rourke","doi":"10.1113/JP287696","DOIUrl":"https://doi.org/10.1113/JP287696","url":null,"abstract":"","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2024-11-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142711586","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Running the clock: new insights into exercise and circadian rhythms for optimal metabolic health","authors":"Corey A. Rynders,&nbsp;Josiane L. Broussard","doi":"10.1113/JP287024","DOIUrl":"10.1113/JP287024","url":null,"abstract":"<p>Circadian rhythms are recurring molecular, physiological and behavioural processes that follow a near 24-h cycle, synchronized with natural transitions between day and night (Acosta-Rodriguez et al., <span>2021</span>). Disruptions to the circadian system impair metabolic regulation, inflammatory responses and tissue repair, contributing to chronic diseases such as type 2 diabetes, cardiometabolic diseases and musculoskeletal disorders (Acosta-Rodriguez et al., <span>2021</span>; Chaput et al., <span>2023</span>). Recent research indicates that altering the timing of key behaviours – such as when we exercise, eat and sleep – leverages circadian biology to promote well-being, although the specific mechanisms are not fully understood (Acosta-Rodriguez et al., <span>2021</span>; Blankenship et al., <span>2021</span>; Petersen et al., <span>2022</span>). An improved understanding of how the timing of behaviours such as exercise and eating interact with endogenous circadian-regulated processes could offer new insights into optimizing health interventions, improving metabolic efficiency and designing preventive strategies for chronic diseases by aligning these behaviours with natural biological rhythms. This knowledge may also help explain individual variability in response to lifestyle interventions, paving the way for more personalized strategies.</p><p>This special issue of <i>The Journal of Physiology</i> entitled ‘Circadian rhythms, exercise and metabolic health’ explores new insights into how exercise (and potentially the time of day that exercise is performed) influences circadian, metabolic, mitochondrial and cardiovascular functions to optimize physical performance and metabolic health, while also examining drivers of individual variability in these responses. Physical exercise has long been regarded as a powerful intervention for treating/preventing conditions such as obesity, cancer and mental health disorders, while also promoting increased healthspan (Blankenship et al., <span>2021</span>). Traditionally, exercise prescription has focused on the manipulation of factors such as frequency, intensity, duration and mode (Blankenship et al., <span>2021</span>). However, as emphasized in this special issue, the <i>timing of exercise</i> may also be strategically harnessed to enhance its benefits. Indeed, skeletal muscle mitochondrial function and physical performance follow daily rhythms, peaking at specific times of day, while disruptions to circadian alignment – such as through simulated night shift work or rapid time zone changes – impair muscle function (Blankenship et al., <span>2021</span>; Chaput et al., <span>2023</span>). As highlighted by the new research in this special issue, aligning exercise with optimal metabolic rhythms offers a promising approach with significant clinical and research implications, bridging the fields of sleep/circadian biology and exercise physiology.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":"602 23","pages":"6367-6371"},"PeriodicalIF":4.7,"publicationDate":"2024-11-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1113/JP287024","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142695834","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}