Pflugers Archiv : European journal of physiology最新文献

{"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}

{"title":"Automated patch-clamp recordings for detecting activators and inhibitors of the epithelial sodium channel (ENaC).","authors":"Florian Sure, Markus Rapedius, Alexei Diakov, Marko Bertog, Alison Obergrussberger, Niels Fertig, Christoph Korbmacher, Alexandr V Ilyaskin","doi":"10.1007/s00424-025-03087-3","DOIUrl":"10.1007/s00424-025-03087-3","url":null,"abstract":"<p><p>The epithelial sodium channel (ENaC) is crucial for sodium absorption in several epithelial tissues including lung and kidney. Its involvement in various renal and pulmonary disorders makes ENaC a potential drug target. High-throughput screening using the automated patch-clamp (APC) technique appears to be a promising approach to discover novel ENaC modulators with (patho-)physiological and therapeutic implications. The aim of this methodological study was to establish APC measurements of ENaC-mediated currents. First, we confirmed functional expression of ENaC in a HEK293 cell line stably transfected with human αβγ-ENaC using conventional manual whole-cell patch-clamp recordings. For APC measurements, a standard enzymatic cell-detachment procedure was used to prepare single cell suspensions. This resulted in a high success rate of APC recordings with amiloride inhibitable ENaC currents. Using a γ-inhibitory peptide and the small molecule ENaC activator S3969, we demonstrate that APC recordings could reveal inhibitory as well as stimulatory effects on ENaC. Interestingly, the enzymatic cell-detachment protocol resulted in partial proteolytic ENaC activation. The portion of proteolytically activated channels could be reduced by prolonged incubation of suspended cells in cell culture medium. This recovery protocol enhanced the relative stimulatory effect of chymotrypsin, a prototypical serine protease known to cause proteolytic ENaC activation. Thus, this protocol may be particularly useful for identifying novel ENaC activators mimicking proteolytic channel activation. In conclusion, we have established a high-throughput screening method for the identification of novel ENaC activators and inhibitors using APC.</p>","PeriodicalId":19954,"journal":{"name":"Pflugers Archiv : European journal of physiology","volume":" ","pages":"857-872"},"PeriodicalIF":2.9,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12092551/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144032747","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":"Sphingosine kinase 1 inhibition aggravates vascular smooth muscle cell calcification.","authors":"Mehdi Razazian, Sheyda Bahiraii, Isratul Jannat, Adéla Tiffner, Georg Beilhack, Bodo Levkau, Jakob Voelkl, Ioana Alesutan","doi":"10.1007/s00424-025-03068-6","DOIUrl":"10.1007/s00424-025-03068-6","url":null,"abstract":"<p><p>Medial vascular calcification is common in chronic kidney disease patients and linked to hyperphosphatemia. Upon phosphate exposure, intricate signaling events orchestrate pro-calcific effects in the vasculature mediated by vascular smooth muscle cells (VSMCs). Sphingosine kinase 1 (SPHK1) produces sphingosine-1-phosphate (S1P) and is associated with complex effects in the vascular system. The present study investigated a possible involvement of SPHK1 in VSMC calcification. Experiments were performed in primary human aortic VSMCs under pro-calcific conditions, with pharmacological inhibition or knockdown of SPHK1 or SPNS2 (a lysolipid transporter involved in cellular S1P export), as well as in Sphk1-deficient and wild-type mice treated with cholecalciferol. In VSMCs, SPHK1 expression was up-regulated by pro-calcific conditions. Calcification medium up-regulated osteogenic marker mRNA expression and activity as well as calcification of VSMCs, effects significantly augmented by co-treatment with the SPHK1 inhibitor SK1-IN-1. SK1-IN-1 alone was sufficient to up-regulate osteogenic signaling in VSMCs during control conditions. Similarly, the SPHK1 inhibitor PF-543 and SPHK1 knockdown up-regulated osteogenic signaling in VSMCs and aggravated VSMC calcification. In contrast, co-treatment with the SPNS2 inhibitor SLF1081851 suppressed osteogenic signaling and calcification of VSMCs, effects abolished by silencing of SPHK1. In addition, Sphk1 deficiency aggravated vascular calcification and aortic osteogenic marker expression in mice after cholecalciferol overload. In conclusion, SPHK1 inhibition, knockdown, or deficiency aggravates vascular pro-calcific signaling and calcification. The reduced calcification after inhibition of S1P export suggests a possible involvement of intracellular S1P, but further studies are required to elucidate the complex roles of SPHKs and S1P signaling in calcifying VSMCs.</p>","PeriodicalId":19954,"journal":{"name":"Pflugers Archiv : European journal of physiology","volume":" ","pages":"815-826"},"PeriodicalIF":2.9,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12092484/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143080789","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":"Consecutive SSCs increase the SSC effect in skinned rat muscle fibres.","authors":"Tobias Elst, Sven Weidner, André Tomalka, Daniel Hahn, Florian Kurt Paternoster, Wolfgang Seiberl, Tobias Siebert","doi":"10.1007/s00424-025-03088-2","DOIUrl":"10.1007/s00424-025-03088-2","url":null,"abstract":"<p><p>Muscle function is essential for generating force and movement, with stretch-shortening cycles (SSCs) playing a fundamental role in the economy of everyday locomotion. Compared with pure shortening contractions, the SSC effect is characterised by increased force, work, and power output during the SSC shortening phase. Few studies have investigated whether SSC effects transfer across consecutive SSCs. Therefore, we investigated SSC effects over three consecutive SSCs in skinned rat muscle fibres by analysing the isometric force immediately before stretch onset (F_onset), the peak force at the end of stretching (F_peak), and the minimum force at the end of shortening (F_min), along with mechanical (Work_SSC) and shortening work (Work_SHO) at different activation levels (20%, 60%, and 100%). Each SSC was followed by an isometric hold phase, allowing force to return to a steady state. Results indicated an increase in both F_peak (20.3%) and Work_SSC (60.9%) from SSC1 to SSC3 across all activation levels tested. At 20% and 60% activation, F_onset, F_min, and Work_SHO increased (range: 4.5-28.5%) from SSC1 to SSC3. However, at 100% activation, F_onset and Work_SHO remained unchanged, while F_min decreased (- 8.5%) from SSC1 to SSC3. These results suggest that the increase in SSC effects at submaximal activation may be primarily due to increased cross-bridge forces. The absence of increases in F_onset, F_min, and Work_SHO at 100% activation suggests that increases in F_peak and Work_SSC may not be attributed to increased cross-bridge force but could instead be caused by additional effects, possibly involving modulation of non-cross-bridge structures, likely titin, and their stiffness.</p>","PeriodicalId":19954,"journal":{"name":"Pflugers Archiv : European journal of physiology","volume":" ","pages":"873-888"},"PeriodicalIF":2.9,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12092553/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144037767","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":"The formation and function of calciprotein particles.","authors":"Edward R Smith, Stephen G Holt","doi":"10.1007/s00424-025-03083-7","DOIUrl":"10.1007/s00424-025-03083-7","url":null,"abstract":"<p><p>Vertebrate extracellular fluids lie below the threshold for spontaneous calcium phosphate (Ca-P_i) precipitation; yet, they remain supersaturated enough to foster crystal growth if unchecked. Calciprotein particles (CPP) and their smaller precursor calciprotein monomers (CPM) have emerged as fast-acting \"mineral buffers\" that mitigate abrupt local oversaturation. Although these complexes typically contain only trace amounts of Ca-P_i relative to total plasma levels, they exhibit remarkably high turnover kinetics, with clearance from the circulation within minutes, far outpacing hormonal loops that operate on timescales of hours to days. By forming ephemeral colloidal assemblies, CPM/CPP help maintain fluid-phase stability and avert uncontrolled crystallization \"accidents\" in microenvironments such as the intestine or bone-remodeling sites. However, under chronic mineral stress, such as in chronic kidney disease, multiple inhibitory factors (e.g., fetuin-A, pyrophosphate) can become deficient, enabling persistent generation of more advanced, crystalline CPP species. These \"modified\" CPP can adsorb additional ligands (e.g., apolipoproteins, microbial remnants, growth factors) and have been linked to inflammatory and pro-calcific changes in vascular and immune cells. Despite their minor quantitative contribution, these rapidly mobilized colloids may exert outsized influence on vascular and skeletal homeostasis, underscoring the need to clarify their origins, biological roles, and potential therapeutic targeting in disorders of mineral metabolism.</p>","PeriodicalId":19954,"journal":{"name":"Pflugers Archiv : European journal of physiology","volume":" ","pages":"753-772"},"PeriodicalIF":2.9,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12092497/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144017128","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":"IRBITs, signaling molecules of great functional diversity.","authors":"Ying Liu, Xuhui Feng, Han Wu, Tianxiang Gui, Mingfeng Fu, Xudong Luo, Lei Zhao, Li-Ming Chen","doi":"10.1007/s00424-025-03095-3","DOIUrl":"https://doi.org/10.1007/s00424-025-03095-3","url":null,"abstract":"<p><p>IRBIT1 and IRBIT2 (collectively, the IRBITs) are signaling molecules with great universality in their expression (ubiquitous distribution in all major tissues in animals) and considerable versatility in their biological functions. Structurally, the IRBITs are highly homologous to S-adenosyl-L-homocysteine hydrolase (AHCY). However, the IRBITs had lost the catalytic activity during the evolution but gained new functions by the addition of a unique N-terminal IRBIT domain. By direct protein interaction, the IRBITs modulate the functions of an array of target proteins of distinct biological functions, ranging from membrane channels and transporters to cytosolic protein kinase, lipid kinases, ribonucleotide reductase, etc. The interaction of the IRBITs with specific target proteins is modulated by the redox couple NAD⁺/NADH. The IRBITs are involved in the regulation of many cellular processes, such as Ca²⁺ signaling, intracellular pH regulation, transepithelial transport of electrolytes and fluid, apoptosis, and DNA metabolism. However, what we have known about the IRBITs is likely just the tip of the iceberg. The present review covers the expression and distribution, physiological and pathological roles, and the structural organization of the IRBITs. It provides a comprehensive review on the binding partners of the IRBITs. Finally, the review addresses the evolution of the IRBITs in reference to the evolution of AHCY.</p>","PeriodicalId":19954,"journal":{"name":"Pflugers Archiv : European journal of physiology","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144187599","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}