Acta Physiologica最新文献_第9页

Towards Understanding the Contribution of Distinct Sodium Currents to Action Potential Formation in Rat Nodose Ganglia 了解不同钠电流对大鼠结节神经节动作电位形成的贡献。

IF 5.6 2区医学

Acta Physiologica Pub Date : 2026-05-15 DOI: 10.1111/apha.70243

Thomas Stiehl

{"title":"Towards Understanding the Contribution of Distinct Sodium Currents to Action Potential Formation in Rat Nodose Ganglia","authors":"Thomas Stiehl","doi":"10.1111/apha.70243","DOIUrl":"10.1111/apha.70243","url":null,"abstract":"The recent study by Zhang and colleagues in Acta Physiologica [1] nicely demonstrates how the combination of classical and more novel experimental approaches provides new insight into the contribution of different voltage-gated sodium channel classes to action potential formation. The principles of action potential formation were established by Hodgkin and Huxley [2] in the unmyelinated squid giant axon. Invertebrates like the giant squid typically possess only one canonical voltage-gated sodium channel type (Nav1) mediating neural excitation [3, 4]. This contrasts with vertebrates, whose neurons express multiple Nav1 paralogs, which can be subdivided into TTX-resistant (TTX-R) and TTX-sensitive (TTX-S), based on whether they can be blocked by tetrodotoxin (TTX) [5].This observation raises the question why vertebrate neurons express multiple voltage-gated sodium-channel isoforms, whereas invertebrate action potential generation relies on a single type. Intriguingly, the vertebrate channel isoforms differ in their biophysical properties and some of them are even dispensable for action potential generation. Zhang et al. [1] addressed this question using Ah- and C-type neurons of isolated and sliced rat nodose ganglia. These ganglia collect visceral information and contain, among others, both unmyelinated C- and myelinated Ah-type neurons. In a first step, the authors employed voltage derivative plots and displacement current phase plots to confirm that two different sequential sodium current components contribute to the action potential in Ah- and C-type neurons (Figure 1A–C). This observation is in line with a scenario known from other systems, where TTX-S channels initiate the depolarization followed by a subsequent recruitment of TTX-R channels [6].In a second series of experiments, Zhang et al. determined the membrane potential where the TTX-R current sets in (kick-in-voltage). This is more intricate than it might seem at first glance. According to textbook electrophysiology, voltage-gated channel opening depends on membrane potential and channel state, and the conductance-voltage relationship is governed by intrinsic gating properties. However, in an experimental setting with limited detection sensitivity, things become more involved: For a given opening probability and a given ion gradient, the number of open channels and thus the ion current are proportional to the number of functional channels in the membrane. Consequently, the more channels in the membrane, the smaller the opening probability at which the current for the first time surpasses the detection threshold. Therefore, the higher the channel density, the more negative the measured kick-in-voltage. If different currents are involved, things become even more challenging. When the TTX-R channels begin to open, the TTX-S current is high and can mask the initially low TTX-R current. Fur","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"242 6","pages":""},"PeriodicalIF":5.6,"publicationDate":"2026-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.70243","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147947317","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}

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Hypertrophic Cardiomyopathy Mutation R723G in MYH7 Enhances Its mRNA-Stability MYH7中肥厚性心肌病突变R723G增强其mrna稳定性

IF 5.6 2区医学

Acta Physiologica Pub Date : 2026-05-15 DOI: 10.1111/apha.70233

Kathrin Kowalski, Luisa Schwarze, Theresia Kraft, Judith Montag

{"title":"Hypertrophic Cardiomyopathy Mutation R723G in MYH7 Enhances Its mRNA-Stability","authors":"Kathrin Kowalski, Luisa Schwarze, Theresia Kraft, Judith Montag","doi":"10.1111/apha.70233","DOIUrl":"10.1111/apha.70233","url":null,"abstract":"Allelic imbalance describes the unequal expression of a gene's two alleles. Whereas it has no effect under normal circumstances, it can aggravate disease course in patients with heterozygous mutations. Hypertrophic cardiomyopathy (HCM), the most common inherited cardiac disorder, is mostly caused by heterozygous mutations in different sarcomeric proteins. One of the most commonly affected proteins is the β-myosin heavy chain (β-MyHC), encoded by MYH7. In several HCM patients, unequal fractions of mutant mRNA and protein have been detected and higher fractions of mutant protein have been associated with a more severe disease course [1, 2]. However, it is unknown which mechanisms cause the unequal allelic ratios in the HCM patients with missense mutations.For HCM-mutation R723G we have shown previously that patients express on average 67% of mutant and 33% of wildtype mRNA and protein [2]. This increased amount of mutant mRNA was also maintained in patient-derived hiPSC-CMs (Figure 1A, n = 6 hiPSC-CM differentiations), in line with previous findings [3]. We have further shown that mutation R723G can alter mRNA secondary structure [4]. We hypothesize that this could alter mRNA turnover and thereby explain the increased allelic fraction of R723G-mRNA. In this case, either production of R723G-mRNA or its stability could be affected. Thus, we compared transcription and degradation of R723G and WT-mRNA to identify potential mechanisms.We first assessed whether the mutant allele is transcribed with a higher probability. We used an allele-specific RNA-FISH analysis for R723G- and WT-mRNA on patient-derived hiPSC-CMs. Active transcription of MYH7 from WT-and R723G encoding alleles was visualized by an intronic probe set as previously described [3]. Additional probes for either WT-MYH7 or R723G-MYH7 were designed and co-hybridized (Figure 1B) using a masked-oligo approach [5]. Detailed description on methodologies will be made available upon request. Specificity of probes was assessed by hybridization to WT-hiPSC-CMs and to RNase-treated tissue, showing no unspecific binding. Sensitivity was ensured by assessing co-localization of WT- and R723G-specific probes with intronic probes and including only experiments with an efficacy above 90% (average efficacy: 92.4% ± 3.4% (n = 4 hybridizations)). Using this technique, we then analyzed the percentage of nuclei without active transcription sites (aTS), with only WT-aTS, only R723G-aTS, and with aTS from both alleles (Figure 1C). Comparable to previous studies where we used one probe set for both alleles [3], we detected 29% ± 9% without aTS. Furthermore, 28% ± 5% of nuclei expressed mRNA only from the WT allele and 23% ± 5% only from the R723G allele. 20% ± 10% of nuclei expressed mRNA from both alleles. Thus, both alleles were transcribed in a comparable fraction ","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"242 6","pages":""},"PeriodicalIF":5.6,"publicationDate":"2026-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13179473/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147947322","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}

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IF 5.6 2区医学

Acta Physiologica Pub Date : 2026-05-15

引用次数: 0

IF 5.6 2区医学

Acta Physiologica Pub Date : 2026-05-15

引用次数: 0

IF 5.6 2区医学

Acta Physiologica Pub Date : 2026-05-14

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IF 5.6 2区医学

Acta Physiologica Pub Date : 2026-05-14

引用次数: 0

Why Physiology Needs to Embrace Structural Biology - The Hot Case of Thermogenic UCP1 为什么生理学需要拥抱结构生物学-产热UCP1的热门案例。

IF 5.6 2区医学

Acta Physiologica Pub Date : 2026-05-14 DOI: 10.1111/apha.70245

Martin Jastroch, Michaela Keuper

{"title":"Why Physiology Needs to Embrace Structural Biology - The Hot Case of Thermogenic UCP1","authors":"Martin Jastroch, Michaela Keuper","doi":"10.1111/apha.70245","DOIUrl":"10.1111/apha.70245","url":null,"abstract":"Scientific progress across biological disciplines has been driven largely by advances in experimental resolution. In particular, physiological research has evolved from classical measurements at the level of whole organisms and organs to molecular analyses in single cells and organelles, where the regulation of gene expression and protein activity is interrogated to elucidate mechanisms underlying homeostasis. Modern physiology has successfully integrated biomechanics, electrophysiology, and biochemistry to resolve processes at subcellular scales. The next frontier lies in the integration of molecular mechanisms at the level of individual proteins, which directly couple regulatory signals to molecular function, for example, by mediating the transport of ions across biological membranes. From a translational perspective, intelligent drug design ultimately depends on precise knowledge of structure–function relationships in the target protein. Any comprehensive understanding of physiological processes, “the full picture,” remains incomplete if these molecular “pixels,” which form the fundamental basis of physiological function, are overlooked.A prominent case for this challenge is the thermogenic mitochondrial uncoupling protein 1 (UCP1) in brown adipose tissue (BAT). UCP1 enables many placental mammals, including humans, to defend their high body temperature in the cold and maintain metabolic homeostasis [1].In this issue of Acta Physiologica, Cavalieri and colleagues comprehensively review current knowledge and remaining unknowns surrounding UCP1 function [2]. While recent cryogenic electron microscopy (cryo-EM) structures of human UCP1 have resolved important structural features [3, 4], the molecular interaction with physiological activators and the mechanism of thermogenic proton transport remain enigmatic [5]. Cavalieri et al. provide a detailed analysis of current UCP1 structure–function relationships and an overview of competing mechanistic models of UCP1 proton translocation, outlining both the progress made and the challenges that persist in understanding one of the grand questions of non-shivering thermogenesis in BAT.BAT itself has a long and rich research history, beginning with the first anatomical description in the 16th century [6], followed by its recognition as a thermogenic organ in the 1960s [7], and the identification of its thermogenic effector protein UCP1 in the late 1970s [8]. Since then, understanding precisely how UCP1 dissipates the mitochondrial proton gradient has driven decades of intensive research. Studies on UCP1 knockout mice, UCP1 loss-of-function mutations in cells, and reconstituted protein in proteoliposomes systems have yielded multiple, and sometimes conflicting models of proton transport and regulation. Key evidence and details from diverse experimental approaches and biological test syste","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"242 6","pages":""},"PeriodicalIF":5.6,"publicationDate":"2026-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.70245","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147939530","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}

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IF 5.6 2区医学

Acta Physiologica Pub Date : 2026-05-14

引用次数: 0

Did You Know: Erythropoiesis Is Regulated by Changes in Posture 你知道吗：红细胞生成受姿势变化的调节。

IF 5.6 2区医学

Acta Physiologica Pub Date : 2026-05-14 DOI: 10.1111/apha.70248

Oscar B. Mazza, Kasper D. Gejl, Steen Larsen, Carsten Lundby

{"title":"Did You Know: Erythropoiesis Is Regulated by Changes in Posture","authors":"Oscar B. Mazza, Kasper D. Gejl, Steen Larsen, Carsten Lundby","doi":"10.1111/apha.70248","DOIUrl":"10.1111/apha.70248","url":null,"abstract":"Blood volume (BV) is among the most tightly regulated variables in the human body and the small variations of only a few percent likely reflect the central role of BV in the maintenance of arterial blood pressure [1]. In turn, changes in blood pressure affect BV, mainly through dynamic plasma volume (PV) modulation, where decreased central venous pressure (CVP) triggers renal release of volume-regulating hormones that promote fluid retention [2-5], while elevations in CVP facilitate renal fluid loss that reduces PV [1, 6]. The potential for CVP to also regulate red blood cell volume (RBCV), however, remains largely unexplored. Members of our group demonstrated that a reduction in CVP—induced by three hours of head-up tilting—increases circulating erythropoietin (EPO) levels in healthy individuals [7] suggesting that a sustained reduction in CVP may promote erythropoiesis. Changes in RBCV are slower than alterations in PV and typically occur over the course of weeks [8]. Accordingly, we tested whether sleeping in a tilted head-up position for five weeks to reduce CVP during the night would facilitate erythropoiesis and expand RBCV. For this purpose, nine males (24.2 ± 5.5 yrs.; 85.4 ± 10.8 kg and 188 ± 7 cm) gave oral and written consent to voluntarily participate in the study. The study was approved by the Ethical Committee of Southern Denmark (project ID: S-20240009) and was conducted in accordance with the Helsinki declaration. In a randomized and counterbalanced order, all participants completed five weeks of either six-degree head-up sleeping (HUS) or horizontal sleeping (CON) in their own homes. Trials were separated by a five-week wash-out period. Sleep quality (scale of 1–10, with 10 being high and 1 being low) and nightly time spent in bed were recorded. For the first (Pre) and last night (Post), as well after one week (1 W) of the respective trials, the participants slept in the laboratory on a mattress identical to the one they were assigned during that specific trial. On these days, before rising from bed, resting systolic and diastolic blood pressure was determined by sphygmomanometry (M3, OMRON, Kyoto, Japan), and a morning forearm vein blood sample was obtained. Plasma for these samples was stored at−20°C and later analyzed for EPO concentrations.Blood volume, intravascular volumes (i.e., RBCV and PV), and total hemoglobin mass were determined by use of the carbon monoxide re-breathing method (Detalo Health, Hørsholm, Denmark) after the first and last night (Pre and Post) of each five-week block. Interactions and main effects regarding intravascular volumes, blood pressure, and EPO concentrations were tested using a linear mixed-effects model, with condition and time as fixed effects, and subject as a random effect. If no interaction was present, the analysis was run again excluding the interaction term. Paired Student's t-tests were used to compare av","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"242 6","pages":""},"PeriodicalIF":5.6,"publicationDate":"2026-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13173307/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147924927","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}

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A Structural Context for the Mechanisms of Uncoupling Protein 1 in Brown Fat Thermogenesis 解偶联蛋白1在棕色脂肪产热机制中的结构背景。

IF 5.6 2区医学

Acta Physiologica Pub Date : 2026-05-14 DOI: 10.1111/apha.70246

Riccardo Cavalieri, Margeoux A. S. Dela Rosa, Camila A. Cotrim, Danielle Copeman, Mehmethan Aris, Callum Eke, Hannah Staggs-Sandy, Paul G. Crichton

{"title":"A Structural Context for the Mechanisms of Uncoupling Protein 1 in Brown Fat Thermogenesis","authors":"Riccardo Cavalieri, Margeoux A. S. Dela Rosa, Camila A. Cotrim, Danielle Copeman, Mehmethan Aris, Callum Eke, Hannah Staggs-Sandy, Paul G. Crichton","doi":"10.1111/apha.70246","DOIUrl":"10.1111/apha.70246","url":null,"abstract":"Uncoupling Protein 1 (UCP1) is a defining feature of brown fat and facilitates the specialized ability of the tissue to generate heat in the process of non-shivering thermogenesis. The protein is activated by fatty acids, which overcome its inhibition by purine nucleotides, to catalyze proton leak across the mitochondrial inner membrane, uncoupling nutrient oxidation from ATP production to release energy as heat. Thermogenesis through this process contributes to thermoregulation in many mammals and can promote nutrient turnover in humans to support metabolic health. UCP1 is a member of the mitochondrial carrier family of solute exchangers. For many years, its underlying mechanisms of activity and regulation have remained unclear. However, recent cryo-EM structures of UCP1 have clarified details on nucleotide inhibition and, with advances in our understanding of the mitochondrial carrier transport mechanism, provided important molecular constraints to rationalize how the protein may operate. Here, we review the molecular nature of UCP1, re-evaluating past structure–function relations in this structural context. Key carrier features and putative novel bonding that likely support state changes in the protein and proton leak activity are highlighted, as well as new hypotheses to explain subtleties in purine nucleotide binding discrimination.","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"242 6","pages":""},"PeriodicalIF":5.6,"publicationDate":"2026-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13173328/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147924946","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}

引用次数: 0