Pflugers Archiv : European journal of physiology最新文献

{"title":"Presynaptic maturation of inhibitory connections onto vasoactive intestinal polypeptide-expressing GABAergic interneurons in the mouse barrel field.","authors":"Clara A Simacek, Sergei Kirischuk, Thomas Mittmann","doi":"10.1007/s00424-025-03101-8","DOIUrl":"https://doi.org/10.1007/s00424-025-03101-8","url":null,"abstract":"<p><p>Vasoactive intestinal polypeptide-expressing inhibitory interneurons (VIP-INs) in the adult barrel cortex are crucial for mediating active whisking (AW) by disinhibiting pyramidal neurons. Past studies have investigated the development of VIP-IN network integration, focusing mainly on the excitatory network or the postsynaptic side of the inhibitory network. Hence, we aimed to explore the inhibitory network integration of VIP-INs, concentrating on the presynaptic side. We addressed this by investigating VIP-INs in three different age groups (postnatal day (P)8-P10, P14-P16, and P30-P36) in Vip-IRES-cre x tdTomato mice with whole-cell patch clamp recordings. By placing a stimulation electrode into L4 of the barrel field, we elicited electrically-evoked inhibitory postsynaptic currents (eIPSCs) in L2/3 VIP-INs following a high-frequency stimulation. We then analysed recorded eIPSCs by applying the binomial model of synaptic transmission. Our results show significant increases in both the number of readily-releasable vesicles and the presynaptic release probability between P9 and P15, suggesting that the inhibitory network integration is at least partially conducted via a presynaptic functional maturation. Despite an increase in the release probability, synaptic depression is decreased at P30-P36 due to an accelerated vesicle replenishment rate within the same time window. Lastly, asynchronous vesicle release decreases in favour of a stimulus-locked signal transmission by P30-P36. Our results suggest a maturation of the inhibitory projections towards a strong, precise, and stimulus-locked inhibition. This can be physiologically relevant to define the temporal precision of AW at the relevant frequencies.</p>","PeriodicalId":19954,"journal":{"name":"Pflugers Archiv : European journal of physiology","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144485507","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Acute activation of human epithelial sodium channel (ENaC) by serum and glucocorticoid inducible kinase 1 (SGK1) requires prior cleavage of the channel's γ-subunit at its proximal cleavage site.","authors":"Alexei Diakov, Florian Sure, Alexandr V Ilyaskin, Christoph Korbmacher","doi":"10.1007/s00424-025-03099-z","DOIUrl":"10.1007/s00424-025-03099-z","url":null,"abstract":"<p><p>Serum and glucocorticoid inducible kinase 1 (SGK1) is a key regulator of the epithelial sodium channel (ENaC). In rat ENaC, the serine residue 621 (S621) in the channel's α-subunit is essential for acute channel activation by SGK1 in outside-out patches. Phosphorylation at S621 probably turns previously silent channels into channels with a high open probability. This is reminiscent of proteolytic ENaC activation resulting from cleavage of the channel's γ-subunit at specific proximal and distal cleavage sites and the release of an inhibitory peptide tract. The first aim of this study was to demonstrate that human ENaC could also be activated acutely by SGK1 and that this depended on the homologous phosphorylation site S594 in human αENaC. Secondly, we wanted to explore whether human ENaC activation by SGK1 depended on the cleavage state of γENaC. Outside-out patch-clamp recordings in Xenopus laevis oocytes expressing human αβγENaC revealed the critical importance of S594 for acute channel activation by SGK1. The latter was not additive to proteolytic channel activation. Interestingly, preventing proximal cleavage in human γENaC completely abolished the stimulatory effect of SGK1. Moreover, tethering the inhibitory peptide in γENaC to its binding site via an engineered disulfide bond prevented stimulation by SGK1. We conclude that ENaC activation by SGK1 requires prior cleavage of γENaC at its proximal cleavage site. Together, these results reveal that SGK1-mediated stimulation of human ENaC is intricately linked to the proteolytic processing of the channel's γ-subunit, emphasizing a previously underappreciated interplay between kinase and protease regulatory pathways.</p>","PeriodicalId":19954,"journal":{"name":"Pflugers Archiv : European journal of physiology","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144336727","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction to: The machinery of healthy vasodilatation: an overview.","authors":"Jana Pourová, Patrícia Dias, Milan Pour, Přemysl Mladěnka","doi":"10.1007/s00424-025-03102-7","DOIUrl":"10.1007/s00424-025-03102-7","url":null,"abstract":"","PeriodicalId":19954,"journal":{"name":"Pflugers Archiv : European journal of physiology","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144333673","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The machinery of healthy vasodilatation: an overview.","authors":"Jana Pourová, Patrícia Dias, Milan Pour, Přemysl Mladěnka","doi":"10.1007/s00424-025-03096-2","DOIUrl":"10.1007/s00424-025-03096-2","url":null,"abstract":"<p><p>Cardiovascular function depends on an adequate vascular tone facilitating appropriate blood flow to individual tissues according to their needs. The tone results from the interplay between vasodilatation and vasoconstriction. Its rapid and efficient regulation is secured by many interconnected physiological mechanisms, both at the level of the vascular smooth muscle and the endothelium. The purpose of this review is to provide an update of the current knowledge on the mechanisms of physiological vasodilatation. First, two principal intracellular signaling pathways linked to the activation of protein kinases PKA and PKG are introduced. Subsequently, the role of endothelium-derived relaxing factors together with the endothelium-dependent hyperpolarization is discussed. The roles of ion channels and gap junctions in the communication between endothelium and vascular smooth muscle cells are particularly discussed. Finally, principal vasodilatory stimuli (mechanical, thermal, chemical) and their mechanisms of action are briefly introduced.</p>","PeriodicalId":19954,"journal":{"name":"Pflugers Archiv : European journal of physiology","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144234778","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Soft tissue calcifications in chronic kidney disease-beyond the vasculature.","authors":"Abul Fajol, Christian Faul","doi":"10.1007/s00424-025-03098-0","DOIUrl":"https://doi.org/10.1007/s00424-025-03098-0","url":null,"abstract":"<p><p>Inappropriate mineralization of soft tissues, also called ectopic calcification, is a well-known pathology in chronic kidney disease (CKD) that is associated with increases in systemic phosphate levels. Vascular calcification is a major contributor to cardiovascular injury and high mortality rates in CKD patients. Therefore, most animal and human studies have focused on the vasculature when describing ectopic calcifications and on the pathologic actions of elevated phosphate on vascular smooth muscle cells in this process. The extent of calcifications within soft tissues beyond the vasculature is not well described, and the involvement of cell types other than vascular smooth muscle cells is not clear. Here we provide a summary of CKD-associated extravascular calcifications in various tissues, which includes the lung, the gastrointestinal system, the liver, the skin, and the brain. Since phosphate elevations and widespread ectopic calcifications do not only occur in the context of CKD, but also in rare genetic disorders that affect the regulators of phosphate metabolism, the cellular transporters of phosphate and the factors protecting from mineral depositions outside of bone, we also discuss these pathologic scenarios. We describe different types of ectopic calcification to flesh out common aspects as well as differences in the potential mechanisms and target cell types. We postulate that phosphate elevations might act in various ways and on various tissues, which together causes a wide spectrum of phosphate-induced pathologies in CKD.</p>","PeriodicalId":19954,"journal":{"name":"Pflugers Archiv : European journal of physiology","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144226190","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Characterization of ROMK cellular heterogeneity along the mouse kidney thick ascending limb.","authors":"Christian Keller, Rui Ramos Santos, Wouter H van Megen, Johannes Loffing","doi":"10.1007/s00424-025-03086-4","DOIUrl":"10.1007/s00424-025-03086-4","url":null,"abstract":"<p><p>The renal thick ascending limb (TAL) plays a key role in water and ion homeostasis. Apical potassium secretion via the renal outer medullary potassium channel (ROMK) is essential for transepithelial sodium reabsorption via the furosemide-sensitive Na-K-2Cl-cotransporter and creates the electrochemical gradient for paracellular ion transport through Claudin tight junction proteins. Interestingly, the TAL exhibits transcriptomic heterogeneity and variable apical ROMK abundance. Single-cell RNA sequencing suggests that the cortical TAL consists of at least three distinct cell types, but whether ROMK distribution aligns with these types remains unclear. We analyzed perfusion-fixed mouse kidneys using RNAscope in situ hybridization (ISH), iterative indirect immunofluorescence imaging (4i multiplexing), and machine learning. ROMK mRNA expression was seen in all TAL cells. In contrast, apical ROMK protein abundance was found on almost all macula densa (MD) cells but was heterogeneous along the rest of the TAL. In the remaining TAL, only about 60% of the TAL cells had strong apical ROMK staining, while 40% lacked apical ROMK but showed weak perinuclear signals. ISH revealed that apical ROMK-positive cells express Ptger3 mRNA, whereas apical ROMK-negative cells express Foxq1 mRNA. Multiplexing analysis showed that ROMK-positive cells form Claudin-10b-positive tight junctions, while ROMK-negative cells form Claudin-16/19-positive junctions and express basolateral Kir4.1. Despite universal ROMK mRNA expression, apical ROMK distribution aligns with molecularly distinct TAL cell types. This unique ROMK expression pattern suggests functional heterogeneity for ROMK along the TAL.</p>","PeriodicalId":19954,"journal":{"name":"Pflugers Archiv : European journal of physiology","volume":" ","pages":"841-856"},"PeriodicalIF":2.9,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12092492/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143985924","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inhibition of Rho-kinase by fasudil contributes to the modulation of the synaptic plasticity response in the rat hippocampus.","authors":"Ercan Babur, Hatice Saray, Cem Süer, Nurcan Dursun","doi":"10.1007/s00424-025-03078-4","DOIUrl":"10.1007/s00424-025-03078-4","url":null,"abstract":"<p><p>Metaplasticity refers to an activity-dependent change in the physiological or biochemical state of neurons that changes their ability to generate subsequently induced synaptic plasticity, such as long-term potentiation (LTP) or long-term depression (LTD). Rho-kinases (ROCK) are known to be important for stable changes in synaptic strength, especially LTP. In this study, we investigated whether LTP inhibition in synapses primed with 1-Hz stimulation was affected by ROCK inhibition in young adult male rats. The study also examined the pattern of tau phosphorylation that occurs during metaplastic regulation, applying into perspective the phosphorylation of tau protein by ROCK. Field potentials consisting of an excitatory postsynaptic potential (fEPSP) and population spike (PS) were recorded from the granule cell layer of the hippocampal dentate gyrus (DG). Metaplastic LTP was induced by strong tetanic stimulation (HFS) of the lateral perforant path after a low-frequency stimulation (LFS) protocol. A glass micropipette was inserted into the granule cell layer of the ipsilateral dentate gyrus to record fEPSP and drug infusion. Drug infusion (saline, n = 8; fasudil, n = 8, 10 µM) was started after the 15-min baseline recording and lasted for 60 min. Total and phosphorylated tau levels were measured in the stimulated hippocampus, which was immediately removed after the electrophysiological recording. LFS prevented the induction of LTP in response to HFS and even produced synaptic LTD in the saline-infused group (83.8 ± 2.6% of the baseline), but moderate potentiation of fEPSP (121.1 ± 7.7% of the baseline) occurred at the end of recording in the experiments where fasudil infusion was performed. LFS caused a comparable early depression, and HFS resulted in a comparable potentiation of the PS amplitude in both groups. Granular cells of the DG failed to exhibit synaptic LTP inhibition in the presence of fasudil, and levels of total and phosphorylated GSK-3β and levels of phosphorylated tau (Ser³⁹⁶ and Ser²⁰²-Thr²⁰⁵) were found to be lower than those of the control group. Based on these findings, it can be concluded that pharmacological inhibition of ROCK results in impaired ability of dentate gyrus neurons to inhibit synaptic LTP, and this result is accompanied by decreased phosphorylation of GSK-3β and tau proteins. The negative effect of fasudil on neuronal function should not be neglected when evaluating its effects as a therapeutic agent for diseases.</p>","PeriodicalId":19954,"journal":{"name":"Pflugers Archiv : European journal of physiology","volume":" ","pages":"787-796"},"PeriodicalIF":2.9,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12092528/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144037466","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impact of aldosterone deficiency on the development of diuretic resistance in mice.","authors":"Daniel Essigke, M Zaher Kalo, Andrea Janessa, Bernhard N Bohnert, Xiaqing Li, Andreas L Birkenfeld, Ferruh Artunc","doi":"10.1007/s00424-025-03082-8","DOIUrl":"10.1007/s00424-025-03082-8","url":null,"abstract":"<p><p>The effect of diuretics can be limited by stimulation of counter-regulatory mechanisms, eventually leading to diuretic resistance. It is thought that the mineralocorticoid aldosterone might contribute to the development of diuretic resistance. To test this, we challenged genetically modified mice with or without a deletion of the gene coding for the aldosterone synthase (AS) with furosemide, hydrochlorothiazide (HCT) and triamterene. Urinary excretion was studied in metabolic cages; kidneys were studied for expression of sodium transporters. In both genotypes, a 4-day treatment with HCT via drinking water (400 mg/l) induced a similar natriuresis and modest loss of body weight < 10%. In contrast, furosemide (125 mg/l) and triamterene (200 mg/l) via drinking water stimulated a significantly higher natriuresis and body weight loss in AS^-/- mice and in addition, triamterene caused massive hyperkalemia > 9 mM and acidosis (pH < 7.0). In AS^+/+ mice, plasma aldosterone concentration tended to increase under furosemide and HCT administration, while triamterene induced a robust ~ sixfold increase. In the kidney, apical targeting and proteolytic activation of the epithelial sodium channel ENaC were stimulated in AS^+/+ mice under triamterene treatment, an effect that was diminished in AS^-/- mice. In conclusion, aldosterone is essentially involved in the development of diuretic resistance to ENaC blockade by triamterene and to a lesser extent to furosemide. In contrast, resistance to HCT was independent of aldosterone.</p>","PeriodicalId":19954,"journal":{"name":"Pflugers Archiv : European journal of physiology","volume":" ","pages":"827-840"},"PeriodicalIF":2.9,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12092488/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144041408","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Emerging roles of PCSK9 in kidney disease: lipid metabolism, megalin regulation and proteinuria.","authors":"Sandra Hummelgaard, Jean-Claude Kresse, Michael Schou Jensen, Simon Glerup, Kathrin Weyer","doi":"10.1007/s00424-025-03069-5","DOIUrl":"10.1007/s00424-025-03069-5","url":null,"abstract":"<p><p>Chronic kidney disease (CKD) is a significant risk factor for cardiovascular disease (CVD). Key features of CKD include proteinuria and reduced glomerular filtration rate, both of which are linked to disease progression and adverse outcomes. Dyslipidemia, a major CVD risk factor, often correlates with CKD severity and is inadequately addressed by conventional therapies. Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a critical role in lipid metabolism by modulating low-density lipoprotein receptor (LDLR) levels and has emerged as a therapeutic target for managing dyslipidemia. PCSK9 inhibitors, including monoclonal antibodies and siRNA, effectively lower LDL cholesterol levels and have demonstrated safety in patients with mild to moderate CKD. Recent findings indicate that PCSK9 aggravates proteinuria by interacting with and downregulating megalin, a proximal tubule receptor essential for protein reabsorption in the kidney. Inhibition of PCSK9 has been shown to preserve megalin levels, reduce proteinuria, and improve the disease phenotype in experimental models. However, conflicting data from preclinical studies underscore the need for further research to clarify the mechanisms underlying PCSK9's role in kidney disease. This review highlights the potential of PCSK9 inhibition in addressing proteinuria and dyslipidemia in CKD, emphasizing its promise as a therapeutic strategy, while addressing current challenges and future directions for research.</p>","PeriodicalId":19954,"journal":{"name":"Pflugers Archiv : European journal of physiology","volume":" ","pages":"773-786"},"PeriodicalIF":2.9,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143441701","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Probiotic Bactolac alleviates depression-like behaviors by modulating BDNF, NLRP3 and MC4R levels, reducing neuroinflammation and promoting neural repair in rat model.","authors":"Musab Işık, Fadime Köse, Özcan Budak, Cansu Özbayer, Rumeysa Keleş Kaya, Sevda Aydın, Aleyna Ceren Küçük, Mehmet Arif Demirci, Songül Doğanay, Cahit Bağcı","doi":"10.1007/s00424-025-03084-6","DOIUrl":"10.1007/s00424-025-03084-6","url":null,"abstract":"<p><p>Depression, a prevalent psychiatric disorder, exerts severe and debilitating impacts on an individual's mental and physical well-being, and it is considered a chronic mental illness. Chronic stress plays an important role in the pathophysiology of depression. Lactobacillus plantarum and Streptococcus thermophilus are psychobiotic bacteria and synthesize some neurotransmitters that play a role in the pathogenesis of depression. In this study, we aimed to investigate the therapeutic effects of Bactolac (Lactobacillus plantarum NBIMCC 8767  + Streptococcus thermophilus NBIMCC 8258) on chronic stress-induced depression in rats. Behavioral tests, including the sucrose preference test, elevated plus maze test, forced swim test, and three-chamber sociability test, were employed to assess depressive and anxiety-like behaviors. The expression level of the 5-HT1A, DRD1, ADRA-2A, GABA-A α1, CNR1, NR3C2, NOD1, NLRP3 and MC4R; BDNF levels, glial activity and intestinal permeability were determined in chronic stress-induced depression in rats. In conclusions, chronic stress decreased the expression levels of 5-HT1A, DRD1, ADRA-2A, GABA-A α1, CNR1, NR3C2, NOD1 and BDNF level; increased the expression levels of NLRP3 and MC4R, caused neurodegeneration and glial activity, ultimately led to depressive effects. Bactolac was effective in reducing depressive-like behaviors according to the results of behavioral tests. Bactolac treatment provided high neuronal survival rate increasing BDNF level, prevented the excessive release of pro-inflammatory cytokines by reducing the expression levels of NLRP3 and MC4R, therefore, prevented the excessive activation of the hypothalamus-pituitary-adrenal (HPA) axis and accordingly, reduced neurodegeneration and glial cell activation in depressed rats. We can suggest that Bactolac supplementation may be beneficial in coping with stress, alleviate the effects of chronic stress and help to protect mental health.</p>","PeriodicalId":19954,"journal":{"name":"Pflugers Archiv : European journal of physiology","volume":" ","pages":"797-814"},"PeriodicalIF":2.9,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12092513/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144064372","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}