Pflugers Archiv : European journal of physiology最新文献

{"title":"ASIC1a as an integrating node in ischemic neurotoxicity: crosstalk with NMDAR and TRPM signaling.","authors":"Ke Lai, Lu-Yang Wang","doi":"10.1007/s00424-026-03225-5","DOIUrl":"https://doi.org/10.1007/s00424-026-03225-5","url":null,"abstract":"<p><p>Ischemic stroke triggers acidosis, glutamate excitotoxicity and oxidative stress, which converge to disturb ionic homeostasis through several cation channels, including acid-sensing ion channel 1a (ASIC1a), N-methyl-D-aspartate receptors (NMDARs) and transient receptor potential melastatin (TRPM) channels. Emerging evidence suggests that ASIC1a functions as a context-dependent integrating node: protons directly gate ASIC1a, glutamate and bilirubin-associated signaling can modulate ASIC1a-dependent injury pathways. ASIC1a directly couples with NMDAR-dependent signaling and indirectly engages TRPM-associated pathways. Here, we discuss the mechanistic basis, therapeutic potential and unresolved questions regarding ASIC1a-associated signaling in ischemic brain injury.</p>","PeriodicalId":19954,"journal":{"name":"Pflugers Archiv : European journal of physiology","volume":"478 11","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149224765","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":"Glutamate tone in preBötzinger complex rhythmogenesis: ambient extracellular glutamate as a candidate excitability bias.","authors":"Enrique Vázquez-Mendoza, Carol Alejandra Olmos-Pastoresa, Donají Chí-Castañeda, María Leonor López-Meraz, Luis Beltran-Parrazal, Consuelo Morgado-Valle","doi":"10.1007/s00424-026-03223-7","DOIUrl":"10.1007/s00424-026-03223-7","url":null,"abstract":"<p><p>The preBötzinger complex (preBötC) is essential for inspiratory rhythm generation, yet the biological processes that repeatedly establish the excitability state required for neuronal recruitment remain incompletely understood. This unresolved issue is reflected in computational models of respiratory rhythmogenesis, which rely on a phenomenological baseline excitability parameter, [Formula: see text], without a defined biological substrate. Ambient extracellular glutamate signaling is well established in other brain regions, but its relevance to the respiratory network remains largely untested. Here, we evaluate the hypothesis that ambient extracellular glutamate outside synaptic clefts-termed glutamate tone-represents one biologically plausible candidate for a distributed extracellular network-state variable in the preBötC. We define glutamate tone as a continuously maintained but dynamically regulated extracellular glutamate signal arising from the balance of glutamate release, diffusion, transporter-mediated clearance, and astrocyte-dependent metabolism. We critically review evidence that extracellular glutamate handling can influence respiratory network activity, while emphasizing that direct evidence for a compartment-specific, rhythmogenesis-relevant glutamate tone remains lacking. We then evaluate candidate glutamate-sensing mechanisms, including peri-/extrasynaptic NMDA receptors and metabotropic glutamate receptors, and place them within the established framework of recurrent excitation, intrinsic membrane conductances, and inhibitory circuitry. We propose that glutamate tone, if present, would not generate the inspiratory burst directly, but could bias the excitability landscape from which neuronal recruitment and synchronization emerge. Finally, we outline experimental criteria for distinguishing a causal excitability bias from glutamate signals that merely reflect ongoing network activity.</p>","PeriodicalId":19954,"journal":{"name":"Pflugers Archiv : European journal of physiology","volume":"478 11","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13675367/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149207438","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":"Revisiting the muscle spindle in ALS: Implications for spinal motor network dysfunction.","authors":"José Castro, Mamede de Carvalho, Michael Swash","doi":"10.1007/s00424-026-03224-6","DOIUrl":"10.1007/s00424-026-03224-6","url":null,"abstract":"<p><p>Amyotrophic lateral sclerosis (ALS) is typically characterized by progressive degeneration of upper and lower motor neurons. However, the contribution of afferent sensory pathways to spinal motor network disorganization has received little attention. Converging human histological evidence from multiple independent laboratories demonstrates that fusimotor (gamma) motor neuron innervation of muscle spindles degenerates in ALS while sensory endings remain morphologically intact at the end organ, although the afferent neurons and ascending sensory pathways are also affected. This dissociation creates unmodulated proprioceptive input. Spindle-derived sensory signals reach spinal interneuron circuits without fusimotor gain-control adjustment, degrading spindles from forward sensory models encoding predicted kinematic states into crude stretch receptors. We propose that this gain-control failure, compounded by the loss of associated alpha-gamma coactivation and beta skeletofusimotor denervation, constitutes an upstream driver of the spinal inhibitory interneuron circuit dysfunction documented by recent electrophysiological studies in ALS. The resulting early disinhibition, followed by maladaptive excitation, mirrors cortical ALS pathophysiology. However, transgenic mouse ALS models show selective sparing of gamma motor neurons, unlike the human disease, constituting a critical translational limitation. We present a temporal model of human ALS, linking fusimotor denervation to progressive disruption of spinal inhibitory and excitatory circuits.</p>","PeriodicalId":19954,"journal":{"name":"Pflugers Archiv : European journal of physiology","volume":"478 11","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149182329","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":"Circadian melatonin suppression and vitamin D deficiency disrupt aortic reactivity via MT1/MT2 and VDR-dependent mechanisms in rats.","authors":"Rebaz S Shekh, Ismail M Maulood","doi":"10.1007/s00424-026-03222-8","DOIUrl":"10.1007/s00424-026-03222-8","url":null,"abstract":"<p><p>Circadian disruption and vitamin D deficiency (VDD) are increasingly prevalent and independently associated with cardiovascular dysfunction. However, their combined impact on vascular reactivity and receptor signaling remains insufficiently defined. This study investigated the independent and interactive effects of melatonin (MEL) suppression induced by continuous light (CL) or pinealectomy (Px) and VDD on vascular contractility, endothelial function, and MT1/vitamin D receptor (VDR) gene expression in rat thoracic aorta. Isolated aortic rings were subjected to cumulative concentration response curves for phenylephrine (PE) and acetylcholine (ACh). Pharmacodynamic parameters, potency (pD₂), maximal efficacy (Emax), and area under the curve (AUC) were calculated. MEL and calcitriol modulation with receptor antagonism was performed to determine receptor dependence. Relative MT1 and VDR mRNA expression was quantified using quantitative reverse transcription polymerase chain reaction (qRT-PCR). CL, Px, and VDD significantly enhanced PE-induced maximal contraction, with the combined deficiency groups exhibiting the greatest augmentation of α₁-adrenergic responsiveness. In contrast, ACh-induced relaxation was selectively impaired under dual-deficiency conditions, characterized by reduced Emax without major changes in pD2, indicating compromised endothelial efficacy rather than altered receptor sensitivity. MEL attenuated vasoconstriction and enhanced relaxation in a receptor-dependent manner, whereas calcitriol potentiated contractility through VDR signaling. Notably, combined CL + VDD produced marked upregulation of MT1 (~ 10-fold) and VDR (~ 108-fold), suggesting compensatory transcriptional remodeling. Circadian disruption and VDD synergistically promote vascular hyperreactivity and endothelial dysfunction. Their convergence amplifies α₁-adrenergic signaling while impairing nitric oxide (NO) mediated relaxation, identifying a mechanistic axis linking modern light exposure and hypovitaminosis D to heightened cardiovascular risk.</p>","PeriodicalId":19954,"journal":{"name":"Pflugers Archiv : European journal of physiology","volume":"478 11","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149183833","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":"Cyclophilin D deficiency exacerbates diet-induced obesity and selectively enhances skeletal muscle mitochondrial respiration in male mice.","authors":"Jazzmin L Hembree, William A Abplanalp, John W Elrod, Paul T Pfluger","doi":"10.1007/s00424-026-03218-4","DOIUrl":"10.1007/s00424-026-03218-4","url":null,"abstract":"<p><p>Mitochondrial dysfunction is a hallmark of obesity-associated metabolic disease, with the mitochondrial permeability transition pore serving as a key regulator of cellular energy homeostasis. Cyclophilin D, encoded by Ppif, is the principal regulatory component of this pore and has been implicated in insulin secretion, adipocyte survival, and whole-body energy balance. However, whether Ppif loss produces a consistent metabolic phenotype when challenged with high fat diet (HFD) exposure, and whether systemic metabolic alterations reflect tissue-specific changes in mitochondrial oxidative capacity, remains unresolved. Here, we characterized male, 21-weeks-old mice with germline Ppif deletion longitudinally over 34 weeks under standard (SD) and HFD using body composition analysis, indirect calorimetry, glucose and insulin tolerance testing and tissue-resolved, Seahorse-based mitochondrial respirometry. Under SD, knockout mice displayed elevated fat mass without differences in food intake or energy expenditure. High-fat feeding progressively amplified this adiposity, with knockout mice developing significantly greater body weight and fat mass than wild-type littermates by weeks 28 and 36. Glucose tolerance and insulin sensitivity remained comparable between genotypes under either diet. ANCOVA revealed significant effects of lean mass (p < 0.001) and genotype (p = 0.017) on energy expenditure, as well as a significant lean mass × genotype interaction (p = 0.025). Consistent with a distinct contribution of lean mass to EE in KO vs. WT mice, we found increased ADP-stimulated mitochondrial respiration in quadriceps of knockout mice under both diets, without corresponding differences in brown adipose tissue or liver, or changes in mitochondrial content across tissues. These findings establish cyclophilin D as a diet- and tissue-specific regulator of energy homeostasis, informing therapeutic strategies targeting the permeability transition pore or cyclophilin D interactome in metabolic disease.</p>","PeriodicalId":19954,"journal":{"name":"Pflugers Archiv : European journal of physiology","volume":"478 11","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13658316/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149170879","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":"Estimating the Starling equation parameters in living humans by using volume kinetic analysis.","authors":"Robert G Hahn","doi":"10.1007/s00424-026-03219-3","DOIUrl":"10.1007/s00424-026-03219-3","url":null,"abstract":"<p><p>The transcapillary filtration of fluid is governed by the Starling forces. The purpose of the present study was to simultaneously estimate all Starling parameters in living humans by using likelihood mathematics. First, the capillary filtration was estimated by volume kinetic analysis at 3,015 time points during 193 intravenous infusion experiments using crystalloid and colloid fluid in adult volunteers and surgical patients placed in the supine position. Second, the obtained capillary filtration and the measured plasma colloid osmotic pressure were entered into a new kinetic analysis to estimate the five remaining parameters in the Starling equation. The result shows that the capillary hydrostatic pressure was 16 mmHg (P_c), the interstitial hydrostatic pressure - 2.2 mmHg (P_i), the interstitial colloid osmotic pressure 1.6 mmHg (π_i), the reflection coefficient 0.79, and the capillary filtration coefficient (K_f) 306 mL/min/mmHg for the whole body when crystalloid volume loading was performed. K_f was significantly lower when colloid fluid (albumin 5% and 20%) was infused, and π_i was lower in patients with subacute inflammation. Association plots showed that P_c was low in hypovolemia and inflammation but markedly higher when albumin was infused. Plots over time suggested that K_f was high early during an infusion, which was probably due to release of nitric oxide due to shear stress, but then decreased gradually. In conclusion, the parameters in the Starling equation could be estimated with acceptable confidence during fluid infusion experiments in humans. Changes of K_f appeared to be key parameter that modulated the capillary filtration rate during volume loading.</p>","PeriodicalId":19954,"journal":{"name":"Pflugers Archiv : European journal of physiology","volume":"478 11","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13658294/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149170943","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":"Differential alternative splicing in skeletal muscle after 14 days immobilization-induced atrophy in young men.","authors":"Aliah Y Aziz, Jamie-Lee M Thompson, Thomas M Doering, Paul J Dunn, Vernon G Coffey","doi":"10.1007/s00424-026-03221-9","DOIUrl":"10.1007/s00424-026-03221-9","url":null,"abstract":"<p><p>Skeletal muscle disuse during injury decreases muscle mass and function. Previous studies have determined differential gene expression associated with atrophy, but changes in alternative splicing (AS) in response to unloading is poorly defined. This study aimed to identify global changes in differential alternative splicing (DAS) in skeletal muscle following unloading. Twenty-one healthy males (26.0 ± 5.7 years; 81.2 ± 11.6 kg) underwent 14 days unilateral knee-brace immobilization. Participants underwent strength and muscle mass assessment before and after the immobilization and vastus lateralis muscle biopsies were taken pre-immobilization, and on days 3 and 14. RNA-sequencing was performed, and DAS events were identified using the rMATS package. Leg strength decreased - 21.5 kg (P < 0.0001) while mid-thigh circumference was reduced ~ 2% (P = 0.016). A total of 157,464 and 159,395 splicing events affecting 15,219 and 15,374 genes identified on day 3 and 14, respectively. Most DAS events occurred in coding sequence regions and were primarily due to exon skipping. A higher number of DAS events were observed by day 14 than day 3, indicating time-dependent regulation. Gene Ontology analysis of DAS at day 14 revealed 37 enriched GO biological processes related to MAPK signalling, mitochondrial function, and organelle organization. Unloading-induced atrophy was associated with widespread changes in AS, particularly in genes linked to muscle maintenance and protein synthesis. AS appears to promote down-regulation of target genes and subsequent differentially enriched biological pathways associated with the functional outcomes of decreased muscle mass and strength. These findings indicate changes in alternative splicing is a regulatory mechanism in muscle wasting during immobilization.</p>","PeriodicalId":19954,"journal":{"name":"Pflugers Archiv : European journal of physiology","volume":"478 11","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13658325/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149168238","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":"Treadmill exercise impedes cognitive decline in type 2 diabetic rats by improving mitochondrial function and modulating the TGF-β/Smad-3 pathway.","authors":"Dibya Sundar Padhy, Nitish Nirala, Sugato Banerjee","doi":"10.1007/s00424-026-03216-6","DOIUrl":"https://doi.org/10.1007/s00424-026-03216-6","url":null,"abstract":"<p><p>Chronic hyperglycemia and cerebral insulin resistance are the major contributors to cognitive impairment in the ageing population. Due to the increased number of the worldwide type - 2 diabetic mellitus (T2DM) population, the prevalence of cognitive decline and dementia has also increased. It is well documented that moderate aerobic exercise dramatically improves cognitive function in individuals with diabetes. However, the impact of exercise on T2DM-associated cognitive decline modulating TGF-β/Smad-3 signalling is yet to be explored. In this study, we assessed the impact of treadmill exercise on cognitive health in a preclinical model of T2DM, focusing on neuroinflammation, mitochondrial function, and the TGF-β/Smad-3 signalling pathway. To develop an experimental type - 2 diabetic model, rats were fed a high-fat diet (HFD), followed by an intraperitoneal injection of a single low dose of streptozotocin (STZ, 35 mg/kg). After confirmation of diabetes, rats underwent moderate-intensity treadmill exercise for 14 weeks. We observed a significant alternation in behavioural patterns in diabetic rats compared to controls, which reversed on exercise treatment. Moreover, chronic Type - 2 diabetes compromises mitochondrial function and increases inflammation in the hippocampal region of the brain. An increase in pro-inflammatory cytokines, such as IL-1β and TNF-α, was observed in the hippocampus of T2DM animals and was reduced by exercise. Oxidative stress is markedly increased in the type - 2 diabetic brain, resulting in compromised mitochondrial function with elevated hippocampal MDA and decreased GSH and ATP levels, which are reversed in the exercise group. Furthermore, we evaluated the role of exercise on TGF-β/Smad-3 signalling in the type - 2 diabetic brain. Exercise suppresses the overexpression of this signalling cascade in the diabetic brain. In summary, moderate-intensity treadmill exercise ameliorated type - 2 diabetes-associated cognitive impairment by decreasing oxidative stress, neuroinflammation, mitochondrial dysfunction and downregulating the TGF-β/Smad-3 signalling pathway.</p>","PeriodicalId":19954,"journal":{"name":"Pflugers Archiv : European journal of physiology","volume":"478 11","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149168769","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":"Sex-specific skeletal muscle fiber atrophy and reduced macrophage inflammation in a rodent transverse aortic constriction model.","authors":"William S Evans, Maria Canellas da Silva, Gabriel Pena, Sarah Kuzmiak-Glancy, Steven J Prior","doi":"10.1007/s00424-026-03220-w","DOIUrl":"https://doi.org/10.1007/s00424-026-03220-w","url":null,"abstract":"<p><p>Heart failure is associated with systemic skeletal muscle remodeling, where sex-specific differences suggest differential peripheral involvement in disease progression. Skeletal muscle macrophages regulate angiogenesis and tissue remodeling and may contribute to early alterations in muscle structure and function during cardiac pressure overload. We tested whether chronic pressure-overload induces sex-specific skeletal muscle remodeling and alters macrophage abundance and paracrine signaling in male and female Sprague Dawley rats that underwent transverse aortic constriction (TAC) or sham surgery at 4 weeks of age and were studied after 40 wk. TAC induced 12% greater heart mass (p = 0.049) and 17% greater heart-to-body mass ratio (p = 0.018) in males, while females showed minimal cardiac remodeling. In extensor digitorum longus (EDL) muscle, TAC males exhibited ~ 10% smaller fiber perimeter corresponding with higher capillary-to-fiber perimeter exchange (p < 0.05 for both), while female TAC rats had no difference in fiber size and 17% lower capillary-to-fiber ratio than female sham (p = 0.033). In soleus muscle, TAC rats had higher capillarization indices (p < 0.05) regardless of sex. Muscle macrophage abundance was 19% lower in TAC males than sham males (p = 0.005). TAC macrophages secreted less MCP-1 (- 35%, p = 0.0058), IL-1β (- 16%, p = 0.0167), TNF-α (- 16%, p = 0.0337), and VEGF-A (- 16%, p = 0.0120) and produced less complex endothelial networks (18% larger mesh size, p = 0.001). These findings indicate that TAC is associated with skeletal muscle remodeling and macrophage immunosuppression, with some changes occurring in a sex-specific manner. This suggests the potential for immune-microvascular coupling in peripheral adaptations to cardiac pressure overload.</p>","PeriodicalId":19954,"journal":{"name":"Pflugers Archiv : European journal of physiology","volume":"478 11","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13653819/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149170657","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":"Acid-sensing ion channels in ischemic stroke: amplifying and constraining neuronal injury in a phase-specific framework.","authors":"Octavia Yifang Weng, Jian-Fei Lu, Xin Qi, Xi Chen, Lu-Yang Wang, Tian-Le Xu","doi":"10.1007/s00424-026-03217-5","DOIUrl":"10.1007/s00424-026-03217-5","url":null,"abstract":"<p><p>For decades, ischemic neuronal death was understood largely as a story about glutamate. Acid-sensing ion channels (ASICs) have revised that account. When cerebral blood flow stops, the penumbra can develop prolonged extracellular acidosis, and experimental studies implicate ASIC1a in mediating sufficient Ca²⁺ entry to injure neurons even when glutamate receptors are blocked, a contribution shaped by channel expression, subunit composition, and the intracellular signaling context. However, sustained acidosis does not necessarily imply sustained channel opening, given ASIC1a desensitization. Besides acidosis, glutamate, polyamines, a paradoxical intracellular alkalization, and oxidative stress can enhance ASIC1a activity or expression, and the channel also signals through a non-conducting route, recruiting RIPK1 to trigger necroptosis independently of ion flux. The relative contributions of these conducting and non-conducting mechanisms in vivo remain incompletely defined. Endogenous mechanisms may constrain injury by internalizing the channel, altering subunit expression, including conditioning-associated ASIC2a upregulation, and degrading ASIC1a through estrogen signaling. We argue that these responses are better understood as constraints on injury than as a genuine survival program, a distinction with mechanistic and therapeutic consequences. Critically, the contribution of these mechanisms may vary over time. The same channel acts as a target of homeostatic regulation before stroke, a driver of death during ischemia, a potential target at reperfusion when acidosis persists but restored flow finally permits drug delivery, and an impediment to repair for weeks afterward. The question in ASIC-targeted neuroprotection is not only whether to inhibit the channel, but also when and for how long.</p>","PeriodicalId":19954,"journal":{"name":"Pflugers Archiv : European journal of physiology","volume":"478 10","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13649881/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149137810","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}