Neurochemistry international最新文献

{"title":"Activation of the β2-adrenoceptor by formoterol induces calcium-dependent exocytosis of synaptic vesicles at the neuromuscular junction in a sex-specific manner","authors":"Kivia B.S. Santos ,&nbsp;Matheus de Castro Fonseca ,&nbsp;Gabriel H.M. Teixeira ,&nbsp;Bruno Sanches ,&nbsp;Silvia Guatimosim ,&nbsp;Leonardo Rossi ,&nbsp;Pablo W. Verly ,&nbsp;Elisa Santiago Pereira ,&nbsp;Walter Cavalcante ,&nbsp;Alexander Birbrair ,&nbsp;Enrrico Bloise ,&nbsp;Juan C. Tapia ,&nbsp;Cristina Guatimosim","doi":"10.1016/j.neuint.2025.106040","DOIUrl":"10.1016/j.neuint.2025.106040","url":null,"abstract":"<div><div>Increasing evidence suggests that the sympathetic nervous system profoundly interacts with skeletal muscle, influencing both muscle fiber function and composition. β₂-ARs, the predominant adrenergic receptor subtype in muscle fibers, have been shown to enhance protein synthesis, reduce protein degradation, facilitate muscle contraction and relaxation, and improve neuromuscular junction (NMJ) transmission upon activation. In this study, we investigated the effects of Formoterol, a highly selective β₂-adrenoceptors (β₂-AR) agonist, on the presynaptic terminal of motor neurons. We used myography, FM1-43 fluorescent dye assays, and transmission electron microscopy (TEM) to evaluate the NMJ following β₂-AR activation. We demonstrated that β₂-AR activation by Formoterol enhances muscle contractility and both spontaneous and evoked exocytosis of acetylcholine (ACh)-containing synaptic vesicles at the mouse diaphragm NMJ. Formoterol-induced morphological changes in diaphragmatic NMJs were consistent with increased exo-endocytic activity. Notably, Formoterol-evoked exocytosis displayed sexual dimorphism, with females showing a significantly milder response compared to males. In females, Formoterol-induced synaptic vesicles exocytosis was mediated solely by P/Q-type voltage-activated Ca²⁺ channels, whereas in males, it involved both P/Q-type channels, transient receptor potential channel of the vanilloid subtype (TRPV) 1 calcium channels, and an additional, yet unidentified, component. Orchiectomized males exhibited responses to Formoterol similar to the females, whereas ovariectomy did not modify female drug responses, indicating that male hormonal environment orchestrates the sex-differences herein described. These findings not only highlight the importance of sex-specific mechanisms but also reveal a novel effect of β₂-AR activation directly on presynaptic terminals by Formoterol, enhancing exocytosis at the NMJ and thereby increasing neuromuscular transmission.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"190 ","pages":"Article 106040"},"PeriodicalIF":4.0,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144919857","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Constant light exposure promotes pathogenic tau hyperphosphorylation and phenotypic manifestations in Drosophila disease models","authors":"Prerna Aggarwal ,&nbsp;Virender ,&nbsp;Surajit Sarkar","doi":"10.1016/j.neuint.2025.106060","DOIUrl":"10.1016/j.neuint.2025.106060","url":null,"abstract":"<div><div>Chronic sleep disruption caused by constant artificial light exposure has emerged as both a comorbidity and a precursor of several neurodegenerative disorders, including tauopathies. Tauopathies, a group of neurodegenerative disorders, are characterised by the toxic accumulation of hyperphosphorylated tau in brain neurons. While disturbance in the sleep/wake cycle is an inherent clinical feature of tauopathies, the impact of prolonged light exposure on disease progression and severity has been inadequately investigated. We utilized <em>Drosophila</em> models of human tauopathies to examine the impact of uninterrupted exposure to light on tau-induced phenotypic markers during pathogenesis over a short period of aging. We observed that constant light exposure causes an earlier onset and increased severity of disease-associated phenotypes in an age-dependent manner. We further noted that these aggravated phenotypes are associated with increased pathogenic hyperphosphorylation of tau, leading to the rapid accumulation of relatively larger neurotoxic aggregates in neuronal cells and their subsequent degeneration. Overall, our study demonstrates that unhealthy light exposure accelerates the early onset and severity of tauopathy-related phenotypes, highlighting its potential relevance in developing management strategies for these devastating neurodegenerative disorders.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"190 ","pages":"Article 106060"},"PeriodicalIF":4.0,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145154328","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Imbalance of NKCC1/KCC2 contributes to the pathogenesis of primary focal hyperhidrosis","authors":"Ru-Jie Zheng ,&nbsp;Nan-Long Lin ,&nbsp;Meng-Long Zhang ,&nbsp;Rui-Qin Qiu ,&nbsp;Feng-Qiang Yu ,&nbsp;Xu Li ,&nbsp;Jian-Bo Lin","doi":"10.1016/j.neuint.2025.106043","DOIUrl":"10.1016/j.neuint.2025.106043","url":null,"abstract":"<div><h3>Background</h3><div>Primary focal hyperhidrosis (PFH) is characterized by excessive sweating in localized regions, significantly impacting patients' quality of life. The imbalance between sodium-potassium-chloride cotransporter 1 (NKCC1) and potassium-chloride cotransporter 2 (KCC2) disrupts chloride ion homeostasis, potentially contributing to the pathogenesis of PFH.</div></div><div><h3>Methods</h3><div>Sweat gland tissues from 76 healthy controls and 76 PFH patients were collected. Expression levels of NKCC1 and KCC2 were assessed using quantitative real-time PCR and Western blotting. Primary sweat gland cells isolated from PFH patients (PFH-SG) and controls (NPFH-SG) were subjected to NKCC1 knockdown via lentiviral shRNA transfection. A hyperhidrosis mouse model was induced by intraperitoneal injection of pilocarpine hydrochloride, and mice were pretreated with the NKCC1 inhibitor bumetanide for one week. Sweat secretion, serum acetylcholine, and chloride ion concentrations were measured. Expression levels of aquaporin 5 (AQP5), brain-derived neurotrophic factor (BDNF), and neuregulin-1 (NRG-1) proteins were analyzed.</div></div><div><h3>Results</h3><div>PFH tissues showed significantly elevated NKCC1 and decreased KCC2 expression compared to controls, correlating with lower sweat chloride levels. NKCC1 knockdown in PFH-SG cells reduced elevated AQP5 expression. In vivo, bumetanide treatment markedly reduced sweat secretion, lowered serum acetylcholine, and restored chloride ion concentrations in hyperhidrosis mice. Furthermore, bumetanide treatment significantly decreased expressions of BDNF and NRG-1 in sympathetic ganglia axons, indicating attenuation of sympathetic hyperactivity associated with hyperhidrosis. NKCC1/KCC2 imbalance contributes significantly to PFH pathology.</div></div><div><h3>Conclusions</h3><div>Bumetanide effectively improves this imbalance, reducing excessive sweating and modulating related neurotransmitter signaling, offering potential therapeutic avenues for PFH.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"190 ","pages":"Article 106043"},"PeriodicalIF":4.0,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144937899","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MUSASHI1 promotes tau phosphorylation by activating the p38 MAPK pathway","authors":"Wenshuang Li ,&nbsp;Baomiao Ma ,&nbsp;Xiang Tian ,&nbsp;Qi Xiong ,&nbsp;Mengqi Zhou ,&nbsp;Wei Liu ,&nbsp;Xiji Shu","doi":"10.1016/j.neuint.2025.106066","DOIUrl":"10.1016/j.neuint.2025.106066","url":null,"abstract":"<div><div>Aberrant phosphorylation of the Tau protein represents a critical event in the pathogenesis of Alzheimer's disease (AD); however, therapeutic interventions specifically targeting this modification remain limited. Therefore, a thorough understanding of the molecular mechanisms underlying Tau hyperphosphorylation is essential for the development of effective preventive and therapeutic strategies against AD. The RNA-binding protein MUSASHI1 (MSI1) is recognized for its significant role in neurodevelopment, and previous studies have reported its dysregulated overexpression in the brains of AD patients. In the current investigation, we demonstrate that MSI1 expression progressively increases in parallel with the advancement of Tau pathology in P301S transgenic mouse models. Furthermore, our findings suggest that MSI1 activates the p38 mitogen-activated protein kinase (MAPK) signaling pathway, thereby promoting Tau phosphorylation. Additionally, we have identified two microtubule-associated proteins as novel potential interaction partners of MSI1 within neuronal cells. Collectively, these results reveal a previously uncharacterized mechanism that may contribute to aberrant Tau phosphorylation in AD, offering new directions for future research in this field.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"190 ","pages":"Article 106066"},"PeriodicalIF":4.0,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145211323","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The antidepressant venlafaxine induces upregulation of miR-92 and histological alterations in a chicken embryo model","authors":"Oykum Kaplan-Arabaci ,&nbsp;Denis Zosen ,&nbsp;Diana Domanska ,&nbsp;Sigrid Bjørnstad ,&nbsp;Simone Santini ,&nbsp;Umut Karaca ,&nbsp;Jasmin Andrea Haeckel ,&nbsp;Kristine Dolva ,&nbsp;Zuzana Dančišinová ,&nbsp;Fred Haugen ,&nbsp;Jannike Mørch Andersen ,&nbsp;Ragnhild Elisabeth Paulsen","doi":"10.1016/j.neuint.2025.106056","DOIUrl":"10.1016/j.neuint.2025.106056","url":null,"abstract":"<div><div>Antidepressants are commonly prescribed for treating anxiety disorders and depression, including pregnant patients. These medications influence the absorption and metabolism of key neurotransmitters such as serotonin, norepinephrine, and dopamine. However, many aspects of antidepressant function remain unclear, especially regarding their impact on neurodevelopment when used during pregnancy. To explore this, we employed a 3R-friendly chicken embryo model to investigate the cellular and molecular implications of antidepressants use. We focused on commonly used antidepressants for the study: escitalopram, which is a selective serotonin reuptake inhibitor; and venlafaxine, a serotonin and noradrenaline reuptake inhibitor, both of which are frequently prescribed during pregnancy.</div><div>Drug distribution analysis showed that both antidepressant drugs reached clinical concentrations in the brain of developing chicken embryos and persisted for several hours. High-throughput miRNA-sequencing showed that venlafaxine upregulated 13 different miRNAs in the chicken cerebellum. Specifically, miR-92 and its human ortholog, miR-363, were significantly upregulated in chicken cerebellum and neuronally differentiated human SH-SY5Y cells, respectively. Neurite metrics showed a significant reduction in neurite outgrowth with venlafaxine, but not with escitalopram. Furthermore, venlafaxine caused histological alterations, such as increased white matter and reduced thickness of the cortical and molecular layer in the cerebellum. Both drugs reduced the thickness of the external granular layer and the number of mitotic events, impacting this crucial germinal zone of the brain.</div><div>These findings highlight distinct neurodevelopmental effects of escitalopram and venlafaxine and raise awareness for potential adverse neurological effects in offspring exposed to antidepressants in utero.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"190 ","pages":"Article 106056"},"PeriodicalIF":4.0,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145124128","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Epitranscriptomic dysregulation in neurodegenerative diseases and its implications for disease pathology and mechanisms","authors":"Andrew M. Shafik,&nbsp;Peng Jin","doi":"10.1016/j.neuint.2025.106037","DOIUrl":"10.1016/j.neuint.2025.106037","url":null,"abstract":"<div><div>RNA modifications, collectively referred to as the epitranscriptome, play a crucial role in regulating RNA metabolism, influencing key processes such as splicing, stability, localization, and translation. Increasing evidence now links dysregulation of the epitranscriptome to neurodegenerative diseases. In this review, we focus on four RNA modifications and their influence on neurodegenerative pathways, including synaptic function, neuroinflammatory signaling, and stress granule formation. These findings highlight the complex and multifaceted roles that RNA modifications play in neurodegeneration, emphasizing their emerging potential as biomarkers and therapeutic targets.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"190 ","pages":"Article 106037"},"PeriodicalIF":4.0,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144896186","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impaired lysosomal proteolysis in developing neurons induces protein aggregation and disrupts morphogenesis and neuromaturation","authors":"Yinping Zhou ,&nbsp;Yuuki Fujiwara ,&nbsp;Mai Shirazaki ,&nbsp;Xiaoye Tian ,&nbsp;Gen Igarashi ,&nbsp;Hiroto Yamauchi ,&nbsp;Kazunori Imaizumi ,&nbsp;Hideki Hayakawa ,&nbsp;Ko Miyoshi ,&nbsp;Taiichi Katayama","doi":"10.1016/j.neuint.2025.106048","DOIUrl":"10.1016/j.neuint.2025.106048","url":null,"abstract":"<div><div>Lysosomes play a central role in the degradation of intracellular substances. Through this degradative capacity, lysosomes contribute to biological homeostasis and are particularly critical for the maintenance and function of neurons. Deficiencies in various lysosomal proteins cause a group of conditions known as lysosomal storage disorders, which often present with developmental delay and other neurological symptoms. In addition, defects in lysosomal function and the autophagic pathways that deliver intracellular substrates to lysosomes have been linked to neurodevelopmental disorders. However, the contribution of lysosomal degradative capacity to neurodevelopment has not been well appreciated. In this study, we aimed to examine the relationship between overall lysosomal proteolytic capacity and neuronal development using primary cultured neurons at early developmental stages. We found that lysosomal protein expression and proteolytic activity increased with neuronal maturation, suggesting that lysosomal proteolysis may play an important role in neuronal development. Treatment of cultured neurons with specific inhibitors of lysosomal proteases during development impaired morphogenesis, as indicated by a significant decrease in neurite length and complexity, along with decreased expression of neuronal lineage marker proteins. Furthermore, we observed that neurons with development impaired by lysosomal protease inhibition accumulated aggregated proteins—some of which were ubiquitinated—in the cytoplasm. These aggregates were enriched with various proteins related to neurodevelopment. These findings provide new insights into the previously underappreciated role of lysosomes in neuronal development.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"190 ","pages":"Article 106048"},"PeriodicalIF":4.0,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144937915","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neuronutritional enhancement of antioxidant defense system through Nrf2/HO1/NQO1 axis in fibromyalgia","authors":"Francesca Inferrera ,&nbsp;Nicla Tranchida ,&nbsp;Roberta Fusco ,&nbsp;Salvatore Cuzzocrea ,&nbsp;Daniela Impellizzeri ,&nbsp;Rosalba Siracusa ,&nbsp;Ramona D'Amico ,&nbsp;Luay Rashan ,&nbsp;Anastasiia Badaeva ,&nbsp;Alexey Danilov ,&nbsp;Vittorio Calabrese ,&nbsp;Rosanna Di Paola ,&nbsp;Marika Cordaro","doi":"10.1016/j.neuint.2025.106057","DOIUrl":"10.1016/j.neuint.2025.106057","url":null,"abstract":"<div><div>Fibromyalgia (FM) is a disorder characterized by chronic widespread musculoskeletal pain, and it is often accompanied by fatigue, sleep disturbance, and cognitive dysfunction. Although pathophysiology is multifactorial, increasing evidence highlights the pivotal role of oxidative stress and mitochondrial dysfunction in the development of this condition. In particular, the Nrf2/HO-1/NQO1 antioxidant axis plays a crucial role in counteracting oxidative damage and maintaining cellular homeostasis. Boswellia (BS) is a genus of plants in the Burseraceae family, which includes around twenty species found across sub-Saharan Africa, the Arabian Peninsula, and the Indian subcontinent. In Ayurvedic medicine, it has traditionally been used in the treatment of diabetes, fever, as well as certain cardiovascular, dermatological, and neurological conditions. Boswellic acids are thought to possess anti-inflammatory, anti-rheumatic, and pain-relieving properties. The purpose of this study was to investigate the beneficial effects of BS extract in a murine model of reserpine-induced FM. Following reserpine administration, markers of oxidative stress, neuroinflammation, and behavioral changes including mechanical allodynia, hyperalgesia, anxiety, and depression-like behaviors were significantly increased. Daily oral administration of BS at a dose of 100 mg/kg effectively restored these pathological changes. BS oral supplementation, by preventing microglia and astrocyte activation, as demonstrated by decreased GFAP and Iba-1 expression, BS decreased neurological inflammation and restored neurotransmitter levels such as norepinephrine, dopamine and serotonin. Futhermore, improved antioxidant defenses by increasing nuclear translocation of Nrf2 and subsequent expression of its downstream targets, HO-1 and NQO1, limiting lipid peroxidation and ROS production. According to behavioral tests, BS significantly reduced the emotional deficit and mechanical sensitivity linked to FM. Our findings indicate that BS integration has neuroprotective effects, acting on oxidative stress and neuroinflammation, and suggesting that it is a viable natural strategy for managing FM symptoms.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"190 ","pages":"Article 106057"},"PeriodicalIF":4.0,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145147246","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Schwann cells as a therapeutic target for amyotrophic lateral sclerosis: A TDP-43 focussed review","authors":"Katherine N. Lewis ,&nbsp;David G. Gonsalvez ,&nbsp;Bradley J. Turner ,&nbsp;Samantha K. Barton","doi":"10.1016/j.neuint.2025.106055","DOIUrl":"10.1016/j.neuint.2025.106055","url":null,"abstract":"<div><div>Amyotrophic lateral sclerosis (ALS) is an incurable, lethal neurodegenerative disease and a proteinopathy with &gt;97 % of cases characterised by pathological accumulation of TDP-43. TDP-43 is ubiquitously expressed and its pathological accumulation has now been identified in non-neuronal cells in both the central and peripheral nervous systems. Thus, the expansion to exploring other cells and their contribution to ALS pathogenesis may be the key to finding more effective treatments. Schwann cells are the myelinating cells of the peripheral nervous system, that encase neuronal axons to propagate action potentials, maintain neuronal health, and respond to neuronal activity in the extracellular environment. Despite Schwann cells being identified to exhibit aberrant TDP-43 proteinopathy in ALS patients, their role in disease remains elusive. Here, we review the potential contributions of Schwann cells to ALS as well as the prospective benefits of harnessing Schwann cells treat the disease.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"190 ","pages":"Article 106055"},"PeriodicalIF":4.0,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145102585","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Two phosphomimetic sites in the GABA transporter GAT1 C-terminus selectively regulate transporter interactions with distinct types of PDZ domains in vitro","authors":"Iveta Koščová,&nbsp;Martina Baliova,&nbsp;Frantisek Jursky","doi":"10.1016/j.neuint.2025.106058","DOIUrl":"10.1016/j.neuint.2025.106058","url":null,"abstract":"<div><div>The GABA transporter GAT1 is a membrane protein that participates in GABA signalling in the brain and certain peripheral tissues. GAT1 contains a C-terminal PDZ motif (-A⁵⁹⁷Y⁵⁹⁸I⁵⁹⁹), previously classified as a type II (ΦXΦ) motif, where PDZ interaction should depend on non-phosphorylatable hydrophobic (Φ) residues at PDZ positions 0 (I⁵⁹⁹) and −2 (A⁵⁹⁷). We recently found that a GAT1 C-terminal peptide unconventionally binds to the PDZ1 domain of syntenin-1 and to the PDZ2 domain of PSD95 by using different PDZ interaction schemes, specifically 0,-1 and 0,-3, respectively. In this work, we used phosphomimetic amino acid mutagenesis to investigate the role of phosphorylatable amino acids in the GAT1 C-terminus in binding to these two domains. The mutagenesis and molecular docking experiments suggested that phosphorylation of tyrosine 598 at PDZ position −1 might affect the interaction with the PDZ1 domain of syntenin-1, but it did not affect the interaction with the PDZ2 domain of PSD95. On the other hand, a phosphomimetic but not a neutral mutation of the remote serine residues 592 and 594 at PDZ positions −7 and −5, respectively, affected the interaction of the GAT1 PDZ motif with the PDZ2 domain of PSD95, but not with the PDZ1 domain of syntenin-1. These findings suggest the existence of at least two domain-specific GAT1 PDZ interaction modes regulated by two distinct potentially phosphorylatable serine and tyrosine residues in the GAT1 C-terminus.</div></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"190 ","pages":"Article 106058"},"PeriodicalIF":4.0,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145136082","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}