Yufeng Huang, Lina Liang, Xuebin Xu, Yin Liu, Feng Gao, Xuelian He, Qing K. Wang
{"title":"Identification of a new gain-of-function variant p.N536Y of KCNMA1 associated with PNKD3 in the Chinese population","authors":"Yufeng Huang, Lina Liang, Xuebin Xu, Yin Liu, Feng Gao, Xuelian He, Qing K. Wang","doi":"10.1111/apha.70039","DOIUrl":"https://doi.org/10.1111/apha.70039","url":null,"abstract":"<p>The high-conductance calcium- and voltage-dependent K<sup>+</sup> potassium channels (BK channel) are important for the electrical excitation of nervous and muscular tissues.<span><sup>1</sup></span> In 2005, we identified the first disease-causing variant in the gene encoding the α-subunit <i>KCNMA1</i> (p.D434G) in this channel and showed that the gain-of-function (GOF) variant of <i>KCNMA1</i> causes paroxysmal nonkinesigenic dyskinesia with or without generalized epilepsy (PNKD3, MIM #609446).<span><sup>2</sup></span> In 2019, we showed that loss of function variants cause Liang-Wang syndrome (MIM #618729) with neurodevelopmental dysfunction of developmental delay, impaired intellectual development, poor or absent language ability, epilepsy, ataxia, and other multi-organ defects.<span><sup>3</sup></span> Both PNKD3 and Liang-Wang syndrome are phenotypically heterogeneous, and detailed genotype–phenotype correlation is critical to genetic testing and counseling.</p><p>To date, only three <i>KCNMA1</i> variants were shown to cause PNKD3, including p.D434G, p.N995S, and p.N536H.<span><sup>2-10</sup></span> Here, we report <i>KCNMA1</i> variants in two new Chinese patients, including a novel variant p.N536Y in the same amino acid as p.N536H and the previously reported variant N995S. In the first patient, PNKD was diagnosed at an age of 2 years and 10 months (Figure 1A), but bilateral hydronephrosis was found at birth. Her developmental milestones were normal during the first 6 months, but then began to slow, and were manifested as low alertness, delayed language acquisition, and poor ability to communicate. When 6 months old, she was admitted to an intensive care unit (ICU) due to high potassium and low sodium, and she developed paroxysmal dyskinesia at the age of one that was successfully treated with carbamazepine, topiramate, and nitrazepam that reduced the frequency and severity of attacks. Whole exome sequencing, also of her parents, identified the de novo <i>KCNMA1</i> variant c.1606A>T, p.N536Y (NM_002247) (Figure 1A,B). The N536 amino acid is highly conserved among different species through evolution (Figure 1C) and located in the Ca<sup>2+</sup>-sensing RCK1 domain (Figure 1D).</p><p>Patch-clamping revealed that variant p.N536Y significantly increases the mean amplitude of <i>I</i><sub><i>BK</i></sub> (Figure 1E) and shifts the G-V curves to more negative potentials by −67 mV at 10 μM [Ca<sup>2+</sup>] (Figure 1E,F), demonstrating that <i>KCNMA1</i> variant p.N536Y is a functional gain-of-function variant. Compared with BK-WT channels, the G-V curves of mutant channels shifted to more negative potentials at all Ca<sup>2+</sup> concentrations. The shift was approximately −105 mV in the presence of 0 μM intracellular [Ca<sup>2+</sup>], −78 mV in the presence of 1 μM intracellular [Ca<sup>2+</sup>], and approximately −67 mV in the presence of 10 μM intracellular [Ca<sup>2+</sup>] (Figure 1G). The data suggest that variant p.N536Y caus","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"241 5","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.70039","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143741041","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}
Casper Homilius, Jacob M. Seefeldt, Jakob Hansen, Roni Nielsen, Frank V. de Paoli, Ebbe Boedtkjer
{"title":"Lactate orchestrates metabolic hemodynamic adaptations through a unique combination of venocontraction, artery relaxation, and positive inotropy","authors":"Casper Homilius, Jacob M. Seefeldt, Jakob Hansen, Roni Nielsen, Frank V. de Paoli, Ebbe Boedtkjer","doi":"10.1111/apha.70037","DOIUrl":"https://doi.org/10.1111/apha.70037","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>H<sup>+</sup> facilitates metabolic blood flow regulation while negatively impacting cardiac contractility. Cardiovascular consequences of conjugate bases accumulating alongside H<sup>+</sup> remain unclear. Here, we evaluate the cardiovascular effects of nine prominent carboxylates—particularly lactate, 3-hydroxybutyrate, and butyrate—linked to metabolic and microbial activity.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Comparing the actions of pH-adjusted Na-carboxylates to equiosmolar NaCl, we study arteries and veins isolated from healthy rats and humans with ischaemic heart disease, isolated perfused rat hearts, and rat cardiovascular function in vivo.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The tested carboxylates generally relax arteries and veins. L-lactate relaxes human and rat arteries up to 70% (EC<sub>50</sub> = 10.1 mM) and rat brachial and mesenteric veins up to 30% of pre-contractions, yet stands out by augmenting contractions of rat femoral, saphenous, and lateral marginal veins and human internal thoracic and great saphenous veins up to 50%. D-lactate shows only minor actions. In isolated perfused hearts, 10 mM L-lactate increases coronary flow (17.1 ± 7.7%) and left ventricular developed pressure (10.1 ± 3.0%) without affecting heart rate. L-lactate infusion in rats—reaching 3.7 ± 0.3 mM in the circulation—increases left ventricular end-diastolic volume (11.3 ± 2.8%), stroke volume (22.6 ± 3.0%), cardiac output (23.4 ± 3.5%), and ejection fraction (10.6 ± 2.0%), and lowers systemic vascular resistance (34.1 ± 3.7%) without influencing blood pressure or heart rate. The ketone body 3-hydroxybutyrate causes lactate accumulation and elevates left ventricular end-diastolic volume in vivo.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Carboxylate metabolites generally relax arteries and veins. L-lactate relaxes arteries, lowering systemic vascular resistance, causes preferential venocontraction with increased ventricular diastolic filling, and elevates cardiac contractility and cardiac output. We propose that L-lactate optimizes cardiovascular function during metabolic disturbances.</p>\u0000 </section>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"241 5","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.70037","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143741103","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}
János Hanics, Evgenii O. Tretiakov, Roman A. Romanov, Anna Gáspárdy, Zsófia Hevesi, Robert Schnell, Tibor Harkany, Alán Alpár
{"title":"Neuronal activity modulates the expression of secretagogin, a Ca2+ sensor protein, during mammalian forebrain development","authors":"János Hanics, Evgenii O. Tretiakov, Roman A. Romanov, Anna Gáspárdy, Zsófia Hevesi, Robert Schnell, Tibor Harkany, Alán Alpár","doi":"10.1111/apha.70031","DOIUrl":"https://doi.org/10.1111/apha.70031","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>Because of their stable expression, some EF-hand Ca<sup>2+</sup>-binding proteins are broadly used as histochemical markers of neurons in the nervous system. Secretagogin is a member of “neuron-specific” Ca<sup>2+</sup>-sensor proteins, yet variations in its expression due, chiefly, to neuronal activity remain ambiguous. We aimed to fill this gap of knowledge both in its use as a cell identity marker and for mechanistic analysis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We mapped secretagogin distribution in human foetal forebrains. Then, <i>Scgn</i>-iCre::Ai9 mice in conjunction with single-cell RNA-seq were used to molecularly characterize cortical secretagogin-expressing neurons. Besides the in vitro manipulation of both SH-SY5Y neuroblastoma cells and primary cortical cultures from foetal mice, the activity dependence of secretagogin expression was also studied upon systemic kainate administration and dark rearing.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>In the mammalian brain, including humans, both transient and stable secretagogin expression sites exist. In the cerebral cortex, we identified deep-layer pyramidal neurons with lifelong expression of secretagogin. Secretagogin expression was affected by neuronal activity: it was delayed in a cohort of human foetuses with Down's syndrome relative to age-matched controls. In mice, dark rearing reduced secretagogin expression in the superior colliculus, a midbrain structure whose development is dependent on topographic visual inputs. In contrast, excitation by both KCl exposure of SH-SY5Y cells and primary cortical neurons in vitro and through systemic kainate administration in mice increased secretagogin expression.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>We suggest that secretagogin expression in neurons is developmentally regulated and activity dependent.</p>\u0000 </section>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"241 5","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.70031","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143741479","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}
Ruizhi Li, Lei Ma, Yingchun Geng, Xiaoxue Chen, Jiaxi Zhu, Hai Zhu, Dong Wang
{"title":"Uteroplacental microvascular remodeling in health and disease","authors":"Ruizhi Li, Lei Ma, Yingchun Geng, Xiaoxue Chen, Jiaxi Zhu, Hai Zhu, Dong Wang","doi":"10.1111/apha.70035","DOIUrl":"https://doi.org/10.1111/apha.70035","url":null,"abstract":"<p>The microvascular system is essential for delivering oxygen and nutrients to tissues while removing metabolic waste. During pregnancy, the uteroplacental microvascular system undergoes extensive remodeling to meet the increased demands of the fetus. Key adaptations include vessel dilation and increases in vascular volume, density, and permeability, all of which ensure adequate placental perfusion while maintaining stable maternal blood pressure. Structural and functional abnormalities in the uteroplacental microvasculature are associated with various gestational complications, posing both immediate and long-term risks to the health of both mother and infant. In this review, we describe the changes in uteroplacental microvessels during pregnancy, discuss the pathogenic mechanisms underlying diseases such as preeclampsia, fetal growth restriction, and gestational diabetes, and summarize current clinical and research approaches for monitoring microvascular health. We also provide an update on research models for gestational microvascular complications and explore solutions to several unresolved challenges. With advancements in research techniques, we anticipate significant progress in understanding and managing these diseases, ultimately leading to new therapeutic strategies to improve maternal and fetal health.</p>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"241 5","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143726945","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":"Epithelial membrane transport and kidney physiology","authors":"Henrik Dimke","doi":"10.1111/apha.70038","DOIUrl":"https://doi.org/10.1111/apha.70038","url":null,"abstract":"<p>Epithelial membrane transport is fundamental to uphold many physiological processes in the kidney and beyond. Since its founding as <i>Skandinavisches Archiv für Physiologie</i> in 1889, <i>Acta Physiologica</i> has published many groundbreaking studies in this field.<span><sup>1, 2</sup></span> These include August Krogh's discoveries on ion absorption in frog skin and the development of the Ussing chamber system. To honor these and many other contributions, a special series on <i>membrane proteins, epithelial transport, and kidney physiology</i> was launched in <i>Acta Physiologica</i> in 2023.<span><sup>2</sup></span> Now, some two years later, the series is drawing to a close, with only a few manuscripts still under review.</p><p>The <i>Acta Physiologica</i> special series has featured both original research articles and full-length reviews, covering recent advances in epithelial transport throughout the various bodily organs, as well as physiological and pathophysiological mechanisms in the kidney. The most recent contributions in this series are highlighted here, and all contributions are now being assembled in a virtual issue.</p><p>A central theme of this series is the molecular machinery that drives epithelial transport and its regulation. With respect to the role of tight junctions and paracellular transport, Pouyiourou et al.<span><sup>3</sup></span> investigated ion permeability profiles of renal paracellular channel-forming claudins. This original study characterized the tight junction proteins in a cell model with minimal endogenous claudin expression.<span><sup>3</sup></span> Their findings offer key insights into how claudins determine tubular ion permeability along the different segments of the nephron, and thus advance our understanding of selective ion transport in the kidney.<span><sup>4</sup></span></p><p>The impact of loop diuretics on renal calcium and magnesium handling is also reviewed. Loop diuretics disrupt the driving force required for paracellular transport in the tubular epithelium, thereby reducing mineral reclamation by the kidney.<span><sup>5</sup></span> In contrast, thiazide diuretics, which are frequently used to reduce blood pressure, limit urinary calcium excretion, and are therefore used to treat kidney stone disease. In this special series, Bargagli et al review the use of thiazides for kidney stone prevention and examine off-target effects on, for example, glucose tolerance.<span><sup>6</sup></span> Another hormone relevant to mineral balance is the anti-aging hormone klotho. For the special series, Grigore et al.<span><sup>7</sup></span> comprehensively review the physiology of klotho-deficient mouse models and provide insights into the role of klotho in the regulation of renal electrolyte transport and mineral balance.</p><p>An original study by Lasaad et al.<span><sup>8</sup></span> explores the role of growth differentiation factor 15 (GDF15) in regulating renal collecting duct cell plasticity in r","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"241 5","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.70038","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143707632","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":"Host-microbiome homeostasis: Unveiling the complex interactions shaping health and disease","authors":"Pontus B. Persson","doi":"10.1111/apha.70034","DOIUrl":"https://doi.org/10.1111/apha.70034","url":null,"abstract":"<p>The relationship between the human body and its microbial communities is becoming increasingly recognized as essential to our overall health. What we once thought of as a mere collection of bacteria, fungi, and other microorganisms now turns out to play a far more active role in maintaining our health or contributing to disease. This connection, known as host-microbiome homeostasis, refers to the balance between our bodies and the microbes residing within us. When this balance is disrupted, it can lead to conditions such as obesity, asthma, epilepsy, and even heart disease. Recent studies in this field shed light on the nature of this coexistence and pave the way toward therapies that harness the power of the microbiome to treat a variety of health issues.</p><p>This special series builds on Acta Physiologica's strong standing in the field<span><sup>1-3</sup></span> and comprises studies delving into different aspects of microbiome research. From using engineered bacteria to fight metabolic diseases to exploring the role of diet and early-life microbial exposure in asthma, these studies highlight just how interconnected our health is with the microbes living in and on us.</p><p>One of the studies, led by Ciocan and Elinav,<span><sup>4</sup></span> explores the idea of using genetically engineered bacteria to change the gut microbiome in ways that can treat disorders like obesity and diabetes. It is a fascinating step toward developing new treatments that could shift the balance of the microbiome for better health. A further article highlights the gut-lung axis and how early-life microbiota might influence asthma. Early-life exposures to microbes may play a major role in determining whether a child is more likely to develop asthma. Factors like how babies are born, whether they are breastfed, and their early diets all influence the development of their gut microbiome, which in turn affects immune responses. This could mean that by targeting the microbiome early on, there may be new opportunities to prevent asthma before it even begins. Pirr and colleagues explore the neonate respiratory microbiome.<span><sup>5</sup></span> For a long time, we assumed that the respiratory tract was relatively sterile; yet, like the gut, it is home to a variety of microbes. The study reveals how the respiratory microbiome develops in newborns and how factors like delivery method, diet, and early infections can shape the microbial communities in the lungs. Understanding how these microbial communities interact with the immune system could lead to new ways to prevent respiratory diseases in children.</p><p>Diet is another area where the microbiome shows its influence, as outlined by Schoeler and his team.<span><sup>6</sup></span> We know that drastic changes in diet can dramatically alter the gut microbiome. This study explores the more subtle effects of typical, everyday dietary variations. By observing how small shifts in diet influence the gut microbiota in both","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"241 4","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.70034","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143689403","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}
Gabriella Blanco, Jianxiang Xue, Linto Thomas, Jessica A. Dominguez Rieg, Dandan Sun, Adrienne Assmus, Robert A. Fenton, Timo Rieg
{"title":"Lack of renal NHE1 exacerbates lithium-induced nephrogenic diabetes insipidus","authors":"Gabriella Blanco, Jianxiang Xue, Linto Thomas, Jessica A. Dominguez Rieg, Dandan Sun, Adrienne Assmus, Robert A. Fenton, Timo Rieg","doi":"10.1111/apha.70029","DOIUrl":"https://doi.org/10.1111/apha.70029","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aims</h3>\u0000 \u0000 <p>The sodium-hydrogen exchanger isoform 1 (NHE1) is important for transepithelial Na<sup>+</sup>/H<sup>+</sup> transport, intracellular pH, and cell volume regulation. NHE1 also transports Li<sup>+</sup>, preferably compared to NHE3, and the lack of NHE3 does not affect renal Li<sup>+</sup> clearance. Therefore, we hypothesized that NHE1 plays a critical role in mediating renal Li<sup>+</sup> effects.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We generated mice lacking NHE1 in epithelial cells throughout the kidney tubule/collecting duct (NHE1<sup>KS-KO</sup>). Physiological phenotyping of NHE1<sup>loxlox</sup> and NHE1<sup>KS-KO</sup> mice was performed under a control diet and after mice received a LiCl-containing diet for 4 weeks. Tissue was harvested at baseline and at the end of the experimental period for quantification of NHE1 and aquaporin-2 abundances.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>In NHE1<sup>loxlox</sup> mice, NHE1 localized to the basolateral membrane of the distal parts of the nephron and collecting duct (principal and intercalated cells). No NHE1 was observed in tubules or collecting ducts of NHE1<sup>KS-KO</sup> mice, and no physiological differences were observed between genotypes under baseline conditions. While both genotypes developed a urinary concentrating defect in response to Li<sup>+</sup>, NHE1<sup>KS-KO</sup> mice drank twice as much, and their urine osmolality was twice as dilute compared with NHE1<sup>loxlox</sup> mice. This was associated with greater hypernatremia in NHE1<sup>KS-KO</sup> mice. Reduced AQP2 and phosphorylation at serine 256 were observed in NHE1<sup>KS-KO</sup> mice. In association with this, AQP2 was more broadly distributed throughout the cytoplasm of NHE1<sup>KS-KO</sup> mice, relative to the defined apical membrane AQP2 distribution seen in NHE1<sup>loxlox</sup> animals.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Lack of NHE1 interferes with the Li<sup>+</sup> handling in principal cells, resulting in exacerbated Li<sup>+</sup>-induced NDI.</p>\u0000 </section>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"241 4","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143689401","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}
Christian Staehr, Victoria Hinkley, Vladimir V. Matchkov, Rajkumar Rajanathan, Line Mathilde B. Hansen, Yvonne Eiby, Nathan Luque, Ian Wright, Stella T. Bjorkman, Stephanie M. Miller, Rohan S. Grimley, Andrew Dettrick, Kirat Chand, Hong L. Nguyen, Nicole M. Jones, Tim V. Murphy, Shaun L. Sandow
{"title":"Hypoxia and ischemic stroke modify cerebrovascular tone by upregulating endothelial BK(Ca) channels—Lessons from rat, pig, mouse, and human","authors":"Christian Staehr, Victoria Hinkley, Vladimir V. Matchkov, Rajkumar Rajanathan, Line Mathilde B. Hansen, Yvonne Eiby, Nathan Luque, Ian Wright, Stella T. Bjorkman, Stephanie M. Miller, Rohan S. Grimley, Andrew Dettrick, Kirat Chand, Hong L. Nguyen, Nicole M. Jones, Tim V. Murphy, Shaun L. Sandow","doi":"10.1111/apha.70030","DOIUrl":"10.1111/apha.70030","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>In animal models and human cerebral arteries, the changes in endothelial cell (EC)-large conductance calcium-activated potassium channel (BK<sub>Ca</sub>) distribution, expression, and function were determined in hypoxia and ischemic stroke. The hypothesis that hypoxia and ischemic stroke induce EC-BK<sub>Ca</sub> in cerebral arteries was examined.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Immunohistochemistry analyzed BK<sub>Ca</sub> expression in EC and smooth muscle (SM) of the middle-cerebral artery (MCA) from rat, piglet, and mouse, and pial arteriole of human. Pressure myography with pharmacological intervention characterized EC-BK<sub>Ca</sub> and TRPV4 function in rat MCA. Electron microscopy determined caveolae density and vessel properties in rat and mouse MCA.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>In rat, pig, and human cerebral vessels, EC-BK<sub>Ca</sub> was absent in normoxia; present after <i>chronic</i> (rat) and <i>acute</i> hypoxia (pig), post-ischemic stroke in human vessels, and after endothelin-1-induced stroke in rats. Mouse MCA EC-BK<sub>Ca</sub> expression increased after <i>acute</i> hypoxia. In rat MCA post-hypoxia and stroke, EC and SMC caveolae density increased, with reduced medial thickness, and unchanged diameter. Caveolae and BK<sub>Ca</sub> did not colocalize. In rat MCA, iberiotoxin (IbTx) potentiated pressure-induced tone in hypoxia/stroke, but not in normoxia. In normoxia, overall MCA tone was unaffected by endothelial removal, but was increased in hypoxia/stroke, where there was no additive effect of endothelial removal and IbTx on tone. Functional TRPV4 was expressed in EC of rat MCA post-stroke.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>In post-hypoxia/stroke, but not in normoxia, EC-BK<sub>Ca</sub> contribute to the regulation of MCA tone. Identifying unique up- and downstream signaling mechanisms associated with EC-BK<sub>Ca</sub> is a potential therapeutic target to control blood flow post-hypoxia/stroke.</p>\u0000 </section>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"241 4","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11926774/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143672973","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":"Les lésions anciennes: Evolution conserves noradrenergic regulation of astroglial homeostatic support","authors":"Alexei Verkhratsky","doi":"10.1111/apha.70032","DOIUrl":"https://doi.org/10.1111/apha.70032","url":null,"abstract":"<p>It is a truth universally acknowledged that every neurone needs an astrocyte to survive and operate. Supportive, homeostatic, and protective neuroglial cells emerged early in evolution together with the centralised nervous system (although some collateral cells of non-neural origin aiding neurones and axons probably existed in even earlier diffuse nervous system of Cnidarians and Ctenophoa). In the February issue of<i>Acta Physiologica</i>, a team of researchers led by Nina Vardjan and Robert Zorec<span><sup>1</sup></span> reveals ancient evolutionary roots of noradrenergic signalling and describes the association with astrocytes, astrocytic Ca<sup>2+</sup> signalling, and astrocyte physiology.</p><p>The very first glial cells were parts of sensory organs, known as sensillas, in invertebrates; incidentally, glial-neuronal sensory organs are common in all species (for example, the organ of Corti, taste buds and olfactory epithelium have ~50% of sustenacular glial cells, which are indispensable for proper sensory function<span><sup>2</sup></span>). The rise of neuroglia reflects the main evolutionary principle of division of functions: neurones are so specialised for the generation of action potentials and synaptic transmission that they cannot sustain the major homeostatic and defensive tasks that define the optimal performance and survival of the nervous tissue. These tasks are fulfilled by neuroglia.<span><sup>3</sup></span></p><p>Astroglial cells, which include many types of parenchymal and radial astrocytes, ependymoglia, and astrocyte-like stem cells, are major homeostatic cells in the central nervous system (CNS) that control and execute various functions at all levels of biological organisation, ranging from molecules to organs. In particular, astrocytes control ion homeostasis of the interstitium (also known as ionostasis) and are the main elements of production, clearance, and catabolism of major neurotransmitters and neuromodulators including L-glutamate, GABA, adenosine, catecholamines, and D-serine.<span><sup>4</sup></span> Astrocytes are electrically non-excitable cells, which employ intercellular ion and second messenger signalling as the substrate of excitability.<span><sup>5</sup></span> Astrocytic ionic signalling is mediated by Ca<sup>2+</sup>, Na<sup>+</sup>, and Cl<sup>−</sup> <span><sup>6</sup></span>; the main second messengers are inositol-1,4,5-trisphosphate (InsP<sub>3</sub>, linked to Ca<sup>2+</sup> signalling) and cyclic AMP (cAMP) regulating multiple intracellular enzymatic cascades.<span><sup>5</sup></span> Coordination of ionic and second messenger excitability is critical for astrocytic function in many physiological and pathophysiological contexts.</p><p>Noradrenergic innervation of the CNS is mainly associated with the locus coeruleus, the brain stem nucleus containing (in humans) ~20 000–50 000 noradrenergic neurones full of neuromelanin that gives them a dark blue appearance. The locus coeruleus was discovere","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"241 4","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.70032","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143633032","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}
Adam N. Keen, James C. McConnell, John J. Mackrill, John Marrin, Alex J. Holsgrove, Janna Crossley, Alex Henderson, Gina L. J. Galli, Dane A. Crossley II, Michael J. Sherratt, Peter Gardner, Holly A. Shiels
{"title":"Cold-induced fibrosis and metabolic remodeling in the turtle (Trachemys scripta) ventricle","authors":"Adam N. Keen, James C. McConnell, John J. Mackrill, John Marrin, Alex J. Holsgrove, Janna Crossley, Alex Henderson, Gina L. J. Galli, Dane A. Crossley II, Michael J. Sherratt, Peter Gardner, Holly A. Shiels","doi":"10.1111/apha.70026","DOIUrl":"https://doi.org/10.1111/apha.70026","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>Cardiac fibrosis contributes to systolic and diastolic dysfunction and can disrupt electrical pathways in the heart. There are currently no therapies that prevent or reverse fibrosis in human cardiac disease. However, animals like freshwater turtles undergo seasonal remodeling of their hearts, demonstrating the plasticity of fibrotic remodeling. In <i>Trachemys scripta</i>, cold temperature affects cardiac load, suppresses metabolism, and triggers a cardiac remodeling response that includes fibrosis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We investigated this remodeling using Fourier transform infrared (FTIR) imaging spectroscopy, together with functional assessment of muscle stiffness, and molecular, histological, and enzymatic analyses in control (25°C) <i>T. scripta</i> and after 8 weeks of cold (5°C) acclimation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>FTIR revealed an increase in absorption bands characteristic of protein, glycogen, and collagen following cold acclimation, with a corresponding decrease in bands characteristic of lipids and phosphates. Histology confirmed these responses. Functionally, micromechanical stiffness of the ventricle increased following cold exposure assessed via atomic force microscopy (AFM) and was associated with decreased activity of regulatory matrix metalloproteinases (MMPs) and increased expression of MMP inhibitors (TMPs) which regulate collagen deposition.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>By defining the structural and metabolic underpinnings of the cold-induced remodeling response in the turtle heart, we show commonalities between metabolic and fibrotic triggers of pathological remodeling in human cardiac disease. We propose the turtle ventricle as a novel model for studying the mechanisms underlying fibrotic and metabolic cardiac remodeling.</p>\u0000 </section>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"241 4","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.70026","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143622666","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}