American journal of physiology. Cell physiology最新文献

{"title":"Redox-sensitive GPCR signaling drives Gq-dependent Ca²⁺ mobilization and cytokine production in human bronchial epithelial cells.","authors":"Jessica Lapiro, Yotesawee Srisomboon, Kayla Law, Scott M O'Grady","doi":"10.1152/ajpcell.00223.2026","DOIUrl":"10.1152/ajpcell.00223.2026","url":null,"abstract":"<p><p>Organic dust (OD) from animal production facilities contains a complex mixture of microbial products, metabolites, and particulates that engage airway epithelial signaling pathways. Here we investigated the mechanisms by which OD extract (ODE) activates immune signaling pathways in human bronchial epithelial cells. ODE rapidly stimulate reactive oxygen species (ROS) generation and a biphasic increase in intracellular Ca²⁺ concentration ([Ca²⁺]_i), consisting of an early transient peak followed by a smaller sustained phase. Antioxidant scavenger pretreatment (glutathione, <i>N</i>-acetyl-cysteine) markedly attenuated both ROS production and Ca²⁺ mobilization, whereas induction of endogenous antioxidant defenses with bardoxolone abolished the response, indicating redox sensitivity. Pharmacologic inhibition of Gqα with YM-254890 suppressed both phases of the Ca²⁺ response, implicating Gq-coupled receptor activation. Consistent with an autocrine amplification mechanism, selective antagonists of histamine (H1), cysteinyl leukotriene (CysLT1 and CysLT2), leukotriene B4 (BLT1), and prostaglandin receptors (EP1) each reduced ODE-evoked Ca²⁺ mobilization. In parallel, inhibitors of histidine decarboxylase, 5-lipoxygenase, and cyclooxygenases (COX-1/COX-2) attenuated Ca²⁺ signaling, supporting rapid endogenous ligand production and secretion. Downstream of Ca²⁺ mobilization, ODE activated protein kinase C alpha/beta (PKCα/β) and protein kinase C delta (PKCδ) and induced robust transcription of proinflammatory cytokine and chemokine mRNAs (IL1β, IL6, IL8, IL33, TNFα) within 2 h of exposure. Enzyme-linked immunosorbent assay confirmed increased secretion of IL-1β, IL-6, IL-8, and IL-33, with differential sensitivity to PKC isoforms and NF-κB inhibition. These findings identify a redox-sensitive G-protein coupled receptor (GPCR) network that amplifies Gq-dependent Ca²⁺ signaling in airway epithelial cells and provides a mechanistic framework for epithelial inflammatory activation following ROS-inducing environmental exposures.<b>NEW & NOTEWORTHY</b> This study investigates how agricultural organic dust promotes airway inflammation. We show that organic dust extract rapidly induces ROS production along with a biphasic Ca²⁺ response through a redox-sensitive, Gq-coupled G-protein coupled receptor (GPCR) network involving histamine, leukotrienes, and prostaglandins. This signaling cascade activates PKC isoforms that trigger production and secretion of inflammatory cytokines, linking oxidative stress to Ca²⁺-dependent inflammatory responses by the airway epithelium following organic dust exposure.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C267-C280"},"PeriodicalIF":5.4,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13359508/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148275646","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pediatric cancer therapy and skeletal muscle growth: an emerging role for satellite cell disruption.","authors":"Cory M Dungan, Rachel R Chiella, Saji Tabrizi, Joe V Chakkalakal, Michael P Wiggs","doi":"10.1152/ajpcell.00304.2026","DOIUrl":"10.1152/ajpcell.00304.2026","url":null,"abstract":"","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C512-C515"},"PeriodicalIF":5.4,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148443863","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impact of ΔF508 CFTR mutation on diaphragm function during acute inflammation.","authors":"Fatemeh Ostadan, Ekaterina Gusev, Feng Liang, Juan Bautista De Sanctis, Danuta Radzioch, Basil J Petrof","doi":"10.1152/ajpcell.00018.2026","DOIUrl":"10.1152/ajpcell.00018.2026","url":null,"abstract":"<p><p>Cystic fibrosis is caused by cystic fibrosis transmembrane conductance regulator (CFTR) mutations and is associated with skeletal muscle dysfunction. Prior work showed exaggerated inflammatory activation of proteolysis pathways in the diaphragms of CFTR-null mice. However, the effects of the more clinically relevant ΔF508 (DF-CFTR) mutation on diaphragm function are unknown. Homozygous DF-CFTR mice (Cftr^tm1EUR) and wild-type littermates received intraperitoneal phosphate-buffered saline or lipopolysaccharide (LPS) (5 mg/kg). After 24 h, we evaluated diaphragm mass and fiber types; expression (mRNA) of cytokines (<i>IL1β</i>, <i>IL6</i>), the unfolded protein response (UPR), and proteolysis (ubiquitin-proteasome, autophagy-lysosome); calpain activity; oxidative stress markers (malondialdehyde, 3-nitrotyrosine); and ex vivo muscle contractility. Oxidative stress markers were higher in DF-CFTR diaphragms at baseline and in response to LPS. Atrogin1 and autophagy markers (<i>LC3B</i>, <i>Gabarapl1</i>) were more strongly induced by LPS in DF-CFTR. Expression of cytokines, UPR, and other proteolysis pathways (<i>MuRF1</i>, calpain) was equivalent. Diaphragm mass, fiber diameter, and fiber type proportions did not differ between groups. Contractile function did not differ at baseline, but only DF-CFTR diaphragms showed reduced force production after LPS. During an acute inflammatory challenge, DF-CFTR diaphragms exhibit exaggerated oxidative stress and proteolysis signaling together with greater force loss. These findings support an increased vulnerability to diaphragm dysfunction linked to the DF-CFTR mutation.<b>NEW & NOTEWORTHY</b> The most common CFTR mutation in cystic fibrosis (CF), ΔF508 (DF-CFTR), was associated with increased oxidative stress in the diaphragm without weakness or atrophy under basal conditions. Acute systemic inflammation triggered further induction of oxidative stress and proteolytic pathways along with greater force loss in the diaphragm, compared with wild-type controls. This previously unrecognized vulnerability of the DF-CFTR diaphragm to systemic inflammation may predispose to respiratory muscle dysfunction in CF, particularly during acute infectious exacerbations.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C348-C357"},"PeriodicalIF":5.4,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148337361","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Copper-dependent redox remodeling of the actin cytoskeleton regulates renal epithelial cell mechanics.","authors":"Pedro Pompeu, Juliana Soares, Íris Ávila Dos Santos, Giuliano Martins Pinheiro, Nicole Jacinto Damasceno, Romênia Ramos Domingues, Glória M R S Grelle, Marcelo Einicker-Lamas, Bruno Pontes, Rafael H F Valverde","doi":"10.1152/ajpcell.00311.2026","DOIUrl":"10.1152/ajpcell.00311.2026","url":null,"abstract":"<p><p>Copper is essential for cellular function but can become toxic in excess. Although its redox and enzymatic roles are well established, how copper availability affects cytoskeletal organization and cell mechanics remains unclear. Here, we show that elevated copper availability increases membrane tether force and F-actin anisotropy in HK-2 proximal tubule cells, consistent with actin cytoskeletal remodeling. Cotreatment with the membrane-permeable reactive oxygen species (ROS) scavenger Tiron reversed copper-induced ROS accumulation and mechanical changes without affecting cell viability, supporting a ROS-dependent mechanism. Quantitative proteomics and post-translational modification profiling (ProteomeXchange: PXD072220) identified coordinated changes in actin-regulatory proteins, including Rab35, methionine sulfoxide reductase B2, casein kinase 2 subunits, and Septin2, together with reduced actin methionine oxidation and copper-sensitive phosphorylation shifts. These findings identify copper-driven redox signaling as a modulator of renal epithelial cell mechanics associated with remodeling of actin-regulatory pathways.<b>NEW & NOTEWORTHY</b> Copper-driven redox signaling remodels the actin cytoskeleton and reprograms the mechanical properties of renal proximal tubule cells. Using optical tweezers, fluorescence imaging, quantitative proteomics, and PTM profiling, we link ROS-dependent mechanical changes to coordinated remodeling of the Rab35/MICAL1/MsrB2 and CK2/Septin2 regulatory axes, establishing copper availability as a modulator of renal epithelial cell mechanics with potential relevance to copper dyshomeostasis in kidney injury.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C516-C532"},"PeriodicalIF":5.4,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148534782","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nonuniform hip adductor muscle deficits in children with cerebral palsy: a comparison between the gracilis and adductor longus.","authors":"Faizan Syed, Latif Omerkhil, Jason J Howard, Christopher Tiessen, Sunnie Vuong, Ruth-Anne Seerattan, Gavin K Thomas, Sach Dabgotra, Isaac Obrigewitsch, Shuyue Liu, Timothy R Leonard, Venus Joumaa, Walter Herzog","doi":"10.1152/ajpcell.00258.2026","DOIUrl":"10.1152/ajpcell.00258.2026","url":null,"abstract":"<p><p>Cerebral palsy (CP) is the most common cause of childhood physical disability and often results in muscle weakness, spasticity, and contractures. Although cellular and sarcomeric impairments have been documented in muscles from children with CP, systematic comparisons of multiple muscles within the same child remain limited. Therefore, we investigated within-subject differences in single muscle fiber mechanics, sarcomeric protein content, and histological properties between patient-paired adductor longus (AL) and gracilis (GR) muscle biopsies obtained from eleven children with severe spastic CP. Maximal active stress and active elastic modulus were significantly lower in AL than GR for both type I and type II muscle fibers, with passive stress also being lower in AL fibers at longer sarcomere lengths (3.0-3.4 µm). AL samples had significantly lower actin and nebulin content compared with GR, whereas myosin and titin did not differ significantly. Fiber cross-sectional area (CSA) was significantly smaller in AL than GR, whereas collagen, fat content, and myosin heavy chain (MHC) isoform distribution did not differ between the two muscles. These findings suggest that muscles with overlapping function can undergo substantially different cellular adaptations within the same child with CP, and treating the hip adductors as a single functional unit may obscure notable muscle-specific adaptations.<b>NEW & NOTEWORTHY</b> To our knowledge, this is the first study to show that two hip adductor muscles from the same children with spastic cerebral palsy differ in single muscle fiber force production and thin-filament protein content. These findings suggest that cellular muscle properties in cerebral palsy can vary substantially between muscles within the same child, even among muscles commonly treated as one functional group.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C441-C454"},"PeriodicalIF":5.4,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148410232","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Loss of lncRNA <i>H19</i> impairs neonatal cardiac regeneration.","authors":"Erika Anneliese Hilbold, Alessia Costa, Sarah Cushman, Maximilian Fuchs, Karina Jansen, Anton Selich, Cheng-Kai Huang, Bernhard Johannes Haubner, Thomas Thum, Christian Bär","doi":"10.1152/ajpcell.00002.2026","DOIUrl":"10.1152/ajpcell.00002.2026","url":null,"abstract":"<p><p>Cardiac regeneration represents a major unmet goal in cardiovascular medicine. Although adult mammalian hearts have very limited capacity to regenerate after injury, newborn mouse hearts can fully restore myocardial structure and function following ischemic damage. This remarkable regenerative ability is rapidly lost within the first postnatal week, but the molecular mechanisms remain poorly understood. Long noncoding RNAs (lncRNAs) have emerged as important regulators of tissue repair and regeneration. Therefore, we aimed to identify lncRNAs involved in neonatal cardiac regeneration and to investigate the function of a candidate lncRNA in regenerating mouse hearts. RNA-sequencing of postnatal day 1 (P1) and P7 mouse hearts revealed approximately 700 significantly differentially expressed lncRNAs. Mapping three neonatal heart RNA-sequencing datasets identified the conserved lncRNA <i>H19</i> as a major nodal point. To assess its potential regenerative function, permanent left anterior descending artery (LAD) ligation surgeries were performed in P1 <i>H19</i> knockout (KO) and wild-type (WT) mice. Myocardial infarction (MI) induction and cardiac function were evaluated by echocardiography. Hearts were harvested for molecular biological and histopathological analyses. Unlike H19WT mice, H19KO neonates failed to recover cardiac function after MI. Although H19WT hearts showed no fibrotic scarring and complete cardiac regeneration, H19KO hearts exhibited increased collagen and <i>Mmp9</i> expression 1-wk post-MI and exhibited fibrotic healing at 1 and 2 wk post-MI. In addition, H19KO mice displayed increased proliferation of noncardiomyocytes and altered immune cells when compared with H19WT mice, indicating substantially impaired cardiac regeneration. In conclusion, <i>H19</i> is essential for complete cardiac regeneration after MI in neonatal mice.<b>NEW & NOTEWORTHY</b> This study highlights the previously unknown role of the conserved lncRNA <i>H19</i> in cardiac regeneration in neonatal mice. The absence of <i>H19</i> leads to fibrosis, impaired functional heart recovery, and altered immune and proliferative responses in newborn mice after ischemic cardiac injury. These findings highlight <i>H19</i> as a promising candidate for improving cardiac regenerative potential and identifying auxiliary factors that aid underlying processes.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C358-C372"},"PeriodicalIF":5.4,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148315099","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sexual dimorphic pattern of renal transporters and channels in spontaneously hypertensive rats.","authors":"Lingyun Ivy Xiong, Ariel M Finch, Donna L Ralph, Babatunde S Anidu, Louise C Evans, Alicia A McDonough","doi":"10.1152/ajpcell.00256.2026","DOIUrl":"10.1152/ajpcell.00256.2026","url":null,"abstract":"<p><p>Male-female differences in the pattern of renal transporters have been reported for normotensive Sprague-Dawley (SD) rats at baseline, when fed with a high-salt diet, and when infused with angiotensin II, which raises blood pressure (AngII-HTN). Whether these sexual dimorphic patterns are evident in spontaneously hypertensive rats (SHR), which exhibit elevated blood pressure from an early age, is unclear. In this study, we profile renal transporters and channels in 14-wk-old male and female SHR using semiquantitative immunoblots, then performed an integrative analysis comparing sexual dimorphisms in renal transporter abundance across conditions. We found that renal transporter profiles exhibit similar patterns of sex differences in hypertensive SHR as reported for normotensive SD, albeit responses are moderated in hypertensive SHR versus SD. In addition, sex differences in transporter abundance are smaller in hypertensive SHR compared with sex differences in hypertensive AngII-HTN SD rats. In particular, along the distal nephron, male and female SHR exhibit greater abundance and activation of transporters and channels, whereas proximal sodium transporter patterns are comparable with those in normotensive SD. These findings are consistent with previous physiological studies reporting that male SHR have blunted acute pressure-natriuresis responses and higher renin-angiotensin-aldosterone system activity. Moreover, comparison with normotensive SD rats fed high-salt diet suggests that renal transporter profiles in male and female SHR may be more a function of the pressure natriuresis response than salt overload.<b>NEW & NOTEWORTHY</b> Hypertension comes in many varieties, instigated by unrelated factors including genetic, hormonal, stress, and environmental factors. Hypertension provides a natriuretic stimulus to match sodium output to intake, which controls circulating volume. This study compares two distinct hypertension models and two sexes: SHR (slowly developing genetic HTN) and AngII infusion hypertension. Results define which sodium transporters' activation drives the hypertension versus which transporters' activity is depressed by the hypertension to maintain fluid and electrolyte balance.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C293-C300"},"PeriodicalIF":5.4,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13427339/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148248750","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The spatiotemporal distribution of Foxi1-expressing pulmonary ionocytes in the mouse airways.","authors":"Sandra Villanueva, Sebastián Hernández-Rivas, Anna Ermund, Brendan Dolan, Gunnar C Hansson, Marcelo A Catalán, Carlos A Flores","doi":"10.1152/ajpcell.00233.2026","DOIUrl":"10.1152/ajpcell.00233.2026","url":null,"abstract":"<p><p>Pulmonary ionocytes are rare epithelial cells that bear the highest amount of mRNA for CFTR and whose function is necessary to regulate airway surface liquid homeostasis. Lineage induction is regulated by the transcription factor forkhead box i1 (Foxi1), but the temporal and spatial localization of Foxi1⁺ cells during airway development and the impact of CFTR mutations remain poorly understood. Here, we used immunofluorescence and RNAscope to detect Foxi1⁺ cells throughout postnatal airway development in male and female mice, from neonatal stages to 1 yr of age, including <i>Cft^r</i>^ΔF508 mutant animals at the adult stage. Foxi1⁺ cells were observed in higher density in the laryngeal subglottis region, decreasing toward the distal trachea, and principally located in the surface epithelium covering intercartilage zones. The Foxi1⁺ cells were observed at postnatal day 7.5, and their appearance correlated with the development of submucosal glands. The distribution of these cells was not altered in the <i>Cft^r</i>^{ΔF508/ΔF508} mutant mouse. These findings demonstrate that pulmonary ionocytes display a highly regionalized distribution pattern in the mouse airway and emerge during a defined postnatal developmental window associated with submucosal gland maturation. Their localization near submucosal gland openings in the mouse trachea and coappearance during development suggest a potential role in regulating submucosal gland secretion and airway epithelial fluid homeostasis.<b>NEW & NOTEWORTHY</b> This study provides the first spatiotemporal map of Foxi1⁺ pulmonary ionocytes in mouse airways. These rare cells, which express the majority of <i>CFTR</i> mRNA, emerge postnatally near developing submucosal glands and concentrate in the laryngeal subglottis during adulthood. Their distribution remains unaltered in <i>Cftr</i>^{ΔF508/ΔF508} mice, suggesting CFTR dysfunction does not disrupt ionocyte patterning.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C281-C292"},"PeriodicalIF":5.4,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148262616","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mitochondrial calcium transport in amino acid metabolism: from nutritional responses to metabolic regulation.","authors":"Marcos Vinícius Caetano, Vitor de Miranda Ramos, Alicia J Kowaltowski","doi":"10.1152/ajpcell.00212.2026","DOIUrl":"10.1152/ajpcell.00212.2026","url":null,"abstract":"<p><p>Mitochondrial calcium (Ca²⁺) transport is a central regulator of cellular metabolism, linking bioenergetics, signaling, and organelle function. Although its role in controlling oxidative phosphorylation and cell fate is well established, emerging evidence indicates that mitochondrial Ca²⁺ handling is also tightly connected to amino acid metabolism and nitrogen balance. In this review, we integrate classical and recent findings to examine how mitochondrial Ca²⁺ transporters, including the mitochondrial calcium uniporter complex, Na⁺/Ca²⁺ exchangers, and H⁺/Ca²⁺ exchange systems, respond to nutritional cues and contribute to metabolic adaptation. We discuss how variations in amino acid availability and dietary protein intake may modulate the expression and activity of Ca²⁺ transport machinery, and explore the emerging role of mitochondrial proteases in regulating transporter turnover and activity, highlighting unexplored questions and future prospects in the field. We discuss how mitochondrial Ca²⁺ fluxes influence amino acid-sensitive processes including autophagy, mitochondrial morphology, and substrate utilization, while also potentially modulating the urea cycle through effects on key enzymes and metabolite transporters. Overall, we find that mitochondrial Ca²⁺ transport is a dynamic interface between nutrient availability and metabolic regulation, with implications for physiology and metabolic disease, but significant gaps remain regarding specific mechanisms within the integration of Ca²⁺ signaling with amino acid-sensing pathways.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C373-C392"},"PeriodicalIF":5.4,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148366521","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"N-linked glycosylation regulates SNAT2 trafficking and stability in pancreatic ductal adenocarcinoma cells.","authors":"Jessica C Koe, Kiana Pashaoskooie, Danisha Johal, Yuxi C Zhong, Caiyun Wu, Seth J Parker","doi":"10.1152/ajpcell.00060.2026","DOIUrl":"10.1152/ajpcell.00060.2026","url":null,"abstract":"<p><p>The sodium-dependent neutral amino acid transporter 2 (SNAT2) is a plasma membrane transporter that facilitates the uptake of small, aliphatic amino acids. Restricting SNAT2-mediated alanine uptake may be a promising therapeutic strategy for various diseases, including pancreatic ductal adenocarcinoma (PDAC). The posttranslational mechanisms regulating the distribution of SNAT2 to intracellular membranes and its turnover remain uncharacterized in the context of PDAC and may be useful to devise future strategies to inhibit SNAT2 function. Human SNAT2 contains three conserved extracellular N-linked glycosylation moieties at N254, N258, and N274. A screen of SNAT2 expression across several human and mouse PDAC cell lines revealed that plasma membrane SNAT2 is exclusively modified by N-linked glycosylation. Preventing SNAT2 N-glycosylation using pharmacological inhibitors or mutagenesis abolished its glycosylation and attenuated its plasma membrane, but not lysosomal, localization. Furthermore, overexpressing glycosylation-deficient SNAT2 in knockout cell lines fails to restore cell proliferative capacity relative to wild-type SNAT2, despite partially rescuing the metabolomic defect associated with SNAT2 deficiency. Using an inducible expression system, we also demonstrate that N-linked glycosylation-deficient SNAT2 mutants exhibit altered degradation kinetics but use similar pathways as wild-type SNAT2 to coordinate its turnover. Our results highlight the importance of N-linked glycosylation for regulating the stability and cell surface expression of nascent SNAT2 in PDAC cells.<b>NEW & NOTEWORTHY</b> This study provides evidence that the localization of human SNAT2 to the plasma membrane requires N-linked glycosylation in PDAC cell lines. To our knowledge, our report is the first to show that localization of SNAT2 to the cell surface is important for supporting PDAC cell proliferation. This work establishes tools to investigate the significance of lysosomal SNAT2 and supports the concept that targeting nutrient transporter glycosylation may represent a viable strategy to limit PDAC growth.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C328-C347"},"PeriodicalIF":5.4,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148343757","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}