Acta Physiologica最新文献

{"title":"Editorial related to the special issue: “Extrarenal functions of the renin-angiotensin-system”","authors":"Rhian M. Touyz, U. Muscha Steckelings","doi":"10.1111/apha.70027","DOIUrl":"https://doi.org/10.1111/apha.70027","url":null,"abstract":"<p>A recent collection of five review articles published in this journal highlights some state-of-the-art research that has been presented at the Gordon Research Conference on Angiotensin in February 2024. These articles feature a broad spectrum of research areas related to the renin-angiotensin-aldosterone system (RAAS), authored by experts in the field.</p><p>Two articles of this collection focus on novel approaches for the understanding of angiotensin receptor signaling.<span><sup>1, 2</sup></span> Gironacci and Bruna-Haupt elucidate how RAAS receptor dimerization with other RAAS- or non-RAAS receptors alters receptor affinity, trafficking, signaling, and biological function.<span><sup>1, 3</sup></span> For example, cross-inhibition is a dimer-specific phenomenon leading to antagonism of one receptor in a dimer by an antagonist specific for the other receptor in the dimer. New drug candidates are in development that target receptor dimers instead of single receptors, making use of dimer-specific crosstalk between receptors. However, the authors also point out that receptor dimerization and its functional consequences are understudied, which means that many drug actions caused by receptor dimerization (e.g. AT<sub>1</sub>-receptor antagonism by beta<sub>2</sub>-adrenergic receptor antagonists<span><sup>4</sup></span>) are underestimated and their potential clinical consequences unknown and not taken into therapeutic consideration.<span><sup>1</sup></span></p><p>Verano-Braga, Steckelings, and co-authors highlight new approaches to study angiotensin receptor signaling through quantitative phosphoproteomics, i.e. the monitoring of all protein phospho- and dephosphorylation events in a cell, as a hypothesis-generating method for identifying so-far unknown angiotensin receptor signaling mechanisms.<span><sup>2</sup></span> The article reviews the literature on phosphoproteomics addressing biased signaling, beta-arrestin-dependent AT<sub>1</sub>-receptor (AT<sub>1</sub>R) signaling, or signaling of receptors of the protective arm of the RAAS, namely AT<sub>2</sub>-receptor (AT<sub>2</sub>R), receptor Mas, and Mas-related G-protein coupled receptor D (MrGD). While all angiotensin receptors are categorized as being G-protein coupled receptors (GPCRs), receptors of the protective arm of the RAAS usually do not induce “classical” GPCR-mediated signaling cascades but rather unconventional, and in large part unknown, pathways, which makes a non-targeted methodology for their identification a useful approach. Extrarenal effects of the protective arm of the RAAS identified by phosphoproteomics include anti-senescence effects (e.g. inhibition of mTOR signaling), effects on histone acetylation with impact on cell cycle control and tumor-suppressor (p53) actions, or effects on glucose homeostasis.<span><sup>5-8</sup></span></p><p>The article highlights future applications of this technology, such as the exploration of cell-specific angiotensin receptor signalin","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"241 4","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.70027","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143622529","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":"Introducing a special issue: Acid–base regulation and sensing in health and disease","authors":"Stine Falsig Pedersen, Ebbe Boedtkjer","doi":"10.1111/apha.70021","DOIUrl":"https://doi.org/10.1111/apha.70021","url":null,"abstract":"<p>Cell metabolism continuously generates acid, primarily in the form of H<sup>+</sup> from fermentation and CO<sub>2</sub> from oxidative phosphorylation. However, the normal physiological functions at all levels of biological organization depend on pH being regulated within narrow ranges. The homeostatic regulation of acid–base status is therefore fundamentally important in virtually all aspects of physiology. At the cellular and organellar level, ion transport proteins import and export acids and bases across membranes, and passive H<sup>+</sup>-buffering systems limit changes in pH upon acid–base challenges and facilitate H<sup>+</sup> movement to and from sites of production and transport. Signaling events—initiated, for example, by H<sup>+</sup>-sensing G-protein coupled receptors, ion channels, and transmembrane or soluble HCO<sub>3</sub><sup>−</sup>-sensing proteins<span><sup>1</sup></span>—control the expression and activity of the pH regulatory systems and produce functional adaptations in response to acid–base disturbances. In vertebrates, acid extruded from cells enters the vasculature and moves via the blood to the lungs and kidneys where it is finally eliminated.</p><p>Given the pivotal physiological importance of acid–base regulation and its disturbances, it is not surprising that key studies on this topic have been published in <i>Acta Physiologica</i>. Over 120 years ago in 1904, when <i>Acta Physiologica</i> was the Skandinavisches Archiv Für Physiologie, August Krogh published pioneering organism-level experiments on cutaneous respiration, that is, the elimination of CO<sub>2</sub> across the frog skin.<span><sup>2</sup></span> Already then, studies of the physiological relevance of pH spanned from organism to molecule, as the same year, Christian Bohr, with Hasselbalch and Krogh, revealed how variation in CO<sub>2</sub> levels (with associated changes in pH) alter O<sub>2</sub> binding to hemoglobin.<span><sup>3</sup></span> This essential observation, widely known as the Bohr effect, was the first demonstration that CO<sub>2</sub>/H<sup>+</sup> binding can alter protein function in a physiologically relevant manner. Since then, the concept of protonation as a posttranslational modification has been studied in great molecular detail. Important examples<span><sup>4</sup></span> now illustrate how pH regulates the function of proteins with protonatable amino acid residues, from enzymes to ion channels to cell adhesion proteins. Thus, we now appreciate a complex landscape of pH sensitivity that extends far beyond the <i>bona fide</i> H<sup>+</sup> sensing receptors.</p><p>More recent work highlights the essential roles that disturbances in acid–base regulation and sensing play in several pathophysiological conditions. This includes solid tumors characterized by extracellular accumulation of acidic metabolic waste products that have been shown to favor cancer progression and limit anti-cancer immunity.<span><sup>1</sup></span> The","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"241 4","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.70021","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143622526","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":"Slow rather than fast calcium events encode physiological inputs and propagate within islets: Lessons from ultrafast imaging on acute pancreatic tissue slices","authors":"Matthieu Raoux, Dorian Chapeau, Jochen Lang","doi":"10.1111/apha.70028","DOIUrl":"https://doi.org/10.1111/apha.70028","url":null,"abstract":"<p>Pancreatic islets are micro-organs, mainly composed of insulin-secreting β cells, which play a central role in nutrient homeostasis and diabetes. They can be viewed as “mini-brains” of glucose homeostasis, as they present networks of excitable cells that express numerous neural proteins<span><sup>1</sup></span> and integrate nutritional, hormonal, and neuronal inputs in real time to continuously provide the amount of insulin required to cover physiological needs. In type 2 diabetes, which accounts for 90% of diabetes cases, both individual and collective β cell activities are impaired. Consequently, many groups have attempted to explore the single-cell and multicellular behavior of β cells for years using either intracellular electrophysiology, which offers high-temporal resolution but is invasive and limited to one cell, or optical methods, mainly Ca<sup>2+</sup> imaging, which provides excellent spatial resolution but very limited temporal resolution, with a typical sampling rate of 0.5–2 Hz. This temporal resolution allows the detection of only slow Ca<sup>2+</sup> events, namely Ca<sup>2+</sup> bursts, and prevents the detection of fast Ca<sup>2+</sup> events, namely Ca<sup>2+</sup> spikes, although Ca<sup>2+</sup> spikes represent the trigger for insulin granule exocytosis. In this issue of <i>Acta Physiologica</i>, Dolenšek et al. present high-temporal-resolution optical measurements (40–178 Hz) of selected islet areas using line scan confocal imaging on acute pancreas slices (i.e. in their native environment) in response to physiological levels of glucose and acetylcholine (Figure 1).<span><sup>2</sup></span> Their detailed characterization of both Ca<sup>2+</sup> bursts and spikes at individual and collective levels offers new insights into the respective roles of these signals in islets, their encoding of glucose levels and cholinergic inputs, and their propagation within the micro-organ, and finally opens new perspectives for understanding islet “mini-brain” networks deregulation in diabetes.</p><p>The classical approach to measure spikes with sufficient temporal resolution in islets has so far been the perforated patch-clamp.<span><sup>3</sup></span> However, this complex and invasive technique allows measurements at the single-cell level rather than the multicellular level and only for a few minutes, whereas islets are stimulated for 2–3h during digestion. Very few ultrafast Ca<sup>2+</sup> measurements on isolated β cells<span><sup>4</sup></span> or whole islets<span><sup>5</sup></span> had been performed prior to this study, but they were limited in time and did not include spike analysis. Dolenšek et al. show now the correspondence between electrical and Ca<sup>2+</sup> events,<span><sup>2</sup></span> consequently, their work paves the way for multicellular optical approaches as an alternative to patch-clamp for laboratories lacking the necessary equipment or expertise.</p><p>Their work provides new insights into islet biology ","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"241 4","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.70028","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143622295","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":"Early signs of neuron autonomous and non-autonomous hyperexcitability in locus coeruleus noradrenergic neurons of a mouse model of tauopathy and Alzheimer's disease","authors":"Zhong-Min Wang,&nbsp;Valentina Grinevich,&nbsp;William R. Meeker,&nbsp;Jie Zhang,&nbsp;María Laura Messi,&nbsp;Evgeny Budygin,&nbsp;Osvaldo Delbono","doi":"10.1111/apha.70022","DOIUrl":"https://doi.org/10.1111/apha.70022","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>The locus coeruleus (LC) is one of the earliest brain regions affected by phosphorylated tau (p-tau) in Alzheimer's disease (AD). Using the P301S mouse model, we investigated the temporal progression of tau pathology and its functional consequences.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Immunohistochemistry was used to assess p-tau deposition in LC noradrenergic neurons at 2–3 and 5–6 months. Electrophysiological recordings evaluated neuronal hyperexcitability, measuring membrane potential, rheobase, and spontaneous action potential (AP) frequency in P301S and wild-type (WT) mice. Fast-scan cyclic voltammetry (FSCV) was used to measure norepinephrine (NE) release. GABA(A) receptor subunit expression was analyzed via immunoblotting.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>P-tau was detected in LC neurons as early as 2–3 months, with a rostral-to-caudal gradient, and by 5–6 months, nearly all LC neurons exhibited p-tau immunoreactivity. P301S neurons showed hyperexcitability, characterized by depolarized membrane potentials, a more negative rheobase, and increased spontaneous AP frequency. Synaptic blockade elicited a reduced increase in AP frequency, suggesting diminished inhibitory tone. GABA(A) α2 subunit expression significantly declined with age in P301S mice, whereas α3 remained unchanged. FSCV showed significantly elevated NE release in P301S mice at 3 and 6 months compared to WT.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>The findings highlight early LC dysfunction in tauopathies, characterized by increased excitability, reduced inhibitory tone, and exaggerated NE release. This hyperactivity may contribute to excitotoxicity and downstream dysfunction in LC-regulated brain regions. Targeting LC hyperactivity and restoring inhibitory signaling could be promising therapeutic strategies for mitigating AD progression.</p>\u0000 </section>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"241 4","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143622528","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 isolated, perfused working heart preparation of the mouse—Advantages and pitfalls","authors":"Diana S. Usai,&nbsp;Ellen Aasum,&nbsp;Morten B. Thomsen","doi":"10.1111/apha.70023","DOIUrl":"https://doi.org/10.1111/apha.70023","url":null,"abstract":"<p>Isolated, perfused hearts are viable for hours outside the body, and important research findings have been made using mouse hearts ex vivo. In the Langendorff perfusion mode, the coronary tree is perfused via retrograde flow of a perfusate down the ascending aorta. Although the Langendorff setup is generally simpler and quicker to establish, the working heart mode allows the heart to function in a more physiologically relevant manner, where the perfusate is directed into the left ventricle via the left atrium. The contracting, fluid-filled ventricle will eject the perfusate into the aorta in a more physiologically relevant manner, lifting the physiological relevance of the contractile and energetic data. The workload on the heart (preload, afterload and heart rate) can be precisely adjusted in the working, isolated heart, and the ventricular performance, for example, end-diastolic and end-systolic pressures, stroke volume, cardiac output, and oxygen consumption can be determined. Moreover, using pressure-volume catheters, ventricular performance can be assessed in great detail. With the present review, we highlight the benefits and drawbacks of the technique and indicate where particular attention must be put when building the working heart setup, designing experiments, executing the studies, and analyzing the obtained data.</p>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"241 4","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.70023","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143602727","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":"Fam163a knockdown and mitochondrial stress in the arcuate nucleus of hypothalamus reduce AgRP neuron activity and differentially regulate mitochondrial dynamics in mice","authors":"Cihan Suleyman Erdogan,&nbsp;Yavuz Yavuz,&nbsp;Huseyin Bugra Ozgun,&nbsp;Volkan Adem Bilgin,&nbsp;Sami Agus,&nbsp;Ugur Faruk Kalkan,&nbsp;Bayram Yilmaz","doi":"10.1111/apha.70020","DOIUrl":"https://doi.org/10.1111/apha.70020","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>Mitochondria play key roles in neuronal activity, particularly in modulating agouti-related protein (AgRP) and proopiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus (ARC), which regulates food intake. FAM163A, a newly identified protein, is suggested to be part of the mitochondrial proteome, though its functions remain largely unknown. This study aimed to investigate the effects of <i>Fam163a</i> knockdown and mitochondrial dysfunction on food intake, AgRP neuron activity, and mitochondrial function in the hypothalamus.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Male C57BL/6 and AgRP-Cre mice received intracranial injections of either <i>Fam163a</i> shRNA, rotenone, or appropriate controls. Behavioral assessments included food intake, locomotor activity, and anxiety-like behaviors. qRT-PCR was used to quantify the expression of the genes related to food intake, mitochondrial biogenesis, dynamics, and oxidative stress. Blood glucose, serum insulin, and leptin levels were measured. Electrophysiological patch-clamp recordings were used to assess the AgRP neuronal activity.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p><i>Fam163a</i> knockdown in the ARC increased the cumulative food intake in short term (first 7 days) without altering the 25-day food intake and significantly increased the <i>Pomc</i> mRNA expression. <i>Fam163a</i> silencing significantly reduced leptin levels. Both <i>Fam163a</i> knockdown and rotenone significantly reduced the firing frequency of AgRP neurons. Neither <i>Fam163a</i> silencing nor rotenone altered locomotor or anxiety-like behaviors. <i>Fam163a</i> knockdown and rotenone differentially altered the expression of mitochondrial biogenesis-, mitophagy-, fusion-, and oxidative stress-related genes.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Hypothalamic FAM163A may play a role in modulating AgRP neuronal activity through regulating mitochondrial biogenesis, dynamics, and redox state. These findings provide insights into the role of FAM163A and mitochondrial stress in the central regulation of metabolism.</p>\u0000 </section>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"241 4","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.70020","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143595466","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":"Heat treatment activates futile calcium cycling in brown adipose tissue to modulate energy metabolism and alters gut microbiota in C57BL/6 mice","authors":"Rong Fan,&nbsp;Galaxie Story,&nbsp;Judy Kim,&nbsp;Zhuoheng Li,&nbsp;Sean T. Bannon,&nbsp;Hyunji Cho,&nbsp;Ravi Ranjan,&nbsp;Young-Cheul Kim,&nbsp;Gwenael Layec,&nbsp;Soonkyu Chung","doi":"10.1111/apha.70025","DOIUrl":"https://doi.org/10.1111/apha.70025","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>Aging decreases the metabolic rate and increases the risk of metabolic diseases, highlighting the need for alternative strategies to improve metabolic health. Heat treatment (HT) has shown various metabolic benefits, but its ability to counteract aging-associated metabolic slowdown remains unclear. This study aimed to investigate the impact of whole-body HT on energy metabolism, explore the potential mechanism involving the heat sensor TRPV1, and examine the modulation of gut microbiota.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Ten-month-old female C57BL/6 mice on a high-fat (HF) diet (45% calories from fat) were exposed to daily HT in a 40–41°C heat chamber for 30 min, 5 days a week for 6 weeks. Metabolic changes, including core body temperature and lipid metabolism transcription in adipose tissue and liver, were assessed. Human brown adipocytes were used to confirm metabolic effects in vitro.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>HT significantly reduced serum lactate dehydrogenase levels, indicating mitigation of tissue damage. HT attenuated weight gain, improved insulin sensitivity, and increased beta-oxidation in the liver and brown fat. In thermogenic adipose tissue, HT enhanced TRPV1 and Ca²⁺/ATPase pump expression, suggesting ATP-dependent calcium cycling, which was confirmed in human brown adipocytes. Interestingly, HT also reduced the firmicutes/bacteroides ratio and altered gut microbiota, suppressing HF diet-enriched microbial genera such as <i>Tuzzerella</i>, <i>Defluviitaleaceae_UCG-011</i>, <i>Alistipes</i>, and <i>Enterorhabdus</i>.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>HT attenuates aging- and diet-associated metabolic slowdown by increasing futile calcium cycling, enhancing energy expenditure, and altering gut microbiota in middle-aged female C57BL/6 mice. HT may offer a promising strategy to improve metabolic health, especially in aging populations.</p>\u0000 </section>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"241 4","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143595465","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":"Trophoblast-specific Deptor knockdown enhances trophoblast nutrient transport and fetal growth in mice","authors":"Lance G. A. Nunes,&nbsp;Rodrigo B. Weingrill,&nbsp;Sam Blessen J. Fredrick,&nbsp;Ramon Lorca,&nbsp;Men-Jean Lee,&nbsp;Shaikh M. Atif,&nbsp;Adam J. Chicco,&nbsp;Fredrick J. Rosario,&nbsp;Johann Urschitz","doi":"10.1111/apha.70012","DOIUrl":"https://doi.org/10.1111/apha.70012","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>Silencing of DEP-domain containing mTOR-interacting protein (DEPTOR), an endogenous inhibitor of the mammalian target of rapamycin (mTOR) pathway, increases mTOR signaling and System A/L amino acid transport activity in cultured primary human trophoblast cells. However, there is no evidence supporting the regulatory role of DEPTOR signaling in placental function in vivo. We hypothesized that trophoblast-specific <i>Deptor</i> knockdown ^(<i>KD</i>) in mice increases trophoblast mTOR signaling, amino acid transport, and enhances fetal growth.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We generated trophoblast-specific <i>Deptor</i>^<i>KD</i> transgenic mice, and at embryonic day 18.5, placentas were analyzed to confirm knockdown efficiency, specificity, and mTOR signaling pathway levels. Trophoblast plasma membrane (TPM) System A/L amino acid transport expression and activity were also determined. We also examined the relationship between birthweight and DEPTOR protein levels in human placentas collected at term from appropriate for gestational age (AGA) and large for gestational age (LGA) pregnancies.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Reducing trophoblast <i>Deptor</i> RNA levels increased placental mTOR signaling, System A/L transporter expression/activity, and fetal growth in mice. Similarly, human LGA placentas displayed decreased DEPTOR protein levels, inversely correlated to birthweight and BMI.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>This is the first report showing that trophoblast-specific <i>Deptor</i>^<i>KD</i> is sufficient to activate mTOR signaling, a master regulator of placental function, which increases the TPM System A and L amino acid transporter expression and activity. We also propose that <i>Deptor</i> expression is mechanistically linked to placental mTOR signaling and fetal growth. Furthermore, modulation of DEPTOR signaling may represent a promising approach to improve outcomes in pregnancies characterized by abnormal fetal growth.</p>\u0000 </section>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"241 4","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143554812","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":"Electromechanical coupling across the gastroduodenal junction","authors":"Sam Simmonds,&nbsp;Jan D. Huizinga,&nbsp;Andrew J. Taberner,&nbsp;Peng Du,&nbsp;Timothy R. Angeli-Gordon","doi":"10.1111/apha.70008","DOIUrl":"https://doi.org/10.1111/apha.70008","url":null,"abstract":"<p>The gastroduodenal junction is uniquely capable of regulating digestive functions in the gastrointestinal system. The pyloric sphincter, which demarcates the stomach from the small intestine, acts as a mechanical and electrical barrier, isolating each organ, thus enabling independent behaviors that are critical for proper digestion. Unique electrical patterns in the stomach, pylorus, and duodenum underpin the distinct contractile patterns of these regions, and improper organization of these mechanical behaviors leads to clinical conditions such as gastroparesis and dumping syndrome. For this reason, the gastroduodenal junction should be a focal point in investigations of novel biomarkers of gastrointestinal dysfunction. This review summarizes the current knowledge of bioelectrical and mechanical characteristics of the gastroduodenal junction, as well as the relevant underlying anatomy. As there is limited documentation of physiological recordings from the gastroduodenal junction of humans, inferences are made from animal studies and from measurements taken from other regions of the gastrointestinal tract, where appropriate. We suggest hypotheses on gastroduodenal electromechanical coupling and propose further studies to support or reject these ideas. Improved physiological understanding of this region, and the advent of novel diagnostic and therapeutic tools are crucial aspects for the future of clinical gastrointestinal medicine.</p>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"241 3","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.70008","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143447147","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":"Canonical or non-canonical, all aspects of G protein-coupled receptor kinase 2 in heart failure","authors":"Abdullah Kaplan,&nbsp;Lana El-Samadi,&nbsp;Rana Zahreddine,&nbsp;Ghadir Amin,&nbsp;George W. Booz,&nbsp;Fouad A. Zouein","doi":"10.1111/apha.70010","DOIUrl":"https://doi.org/10.1111/apha.70010","url":null,"abstract":"<p>G protein-coupled receptor kinase 2 (GRK2) with its multidomain structure performs various crucial cellular functions under both normal and pathological conditions. Overexpression of GRK2 is linked to cardiovascular diseases, and its inhibition or deletion has been shown to be protective. The functions of GRK2 extend beyond G protein-coupled receptor (GPCR) signaling, influencing non-GPCR substrates as well. Increased GRK2 in heart failure (HF) initially may be protective but ultimately leads to maladaptive effects such as GPCR desensitization, insulin resistance, and apoptosis. The multifunctional nature of GRK2, including its action in hypertrophic gene expression, insulin signaling, and cardiac fibrosis, highlights its complex role in HF pathogenesis. Additionally, GRK2 is involved in mitochondrial biogenesis and lipid metabolism. GRK2 also regulates epinephrine secretion from the adrenal gland and its increase in circulating lymphocytes can be used to monitor HF status. Overall, GRK2 is a multifaceted protein with significant implications for HF and the regulation of GRK2 is crucial for understanding and treating cardiovascular diseases.</p>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"241 3","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.70010","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143424234","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}