ACS Chemical Neuroscience最新文献_第7页

Identification of a Lipid-Exposed Extrahelical Binding Site for Positive Allosteric Modulators of the Dopamine D₂ Receptor. 多巴胺D2受体阳性变构调节剂的脂质暴露的螺旋外结合位点的鉴定。

IF 4.1 3区医学

ACS Chemical Neuroscience Pub Date : 2025-06-18 Epub Date: 2025-05-15 DOI: 10.1021/acschemneuro.5c00105

Herman D Lim, Damian Bartuzi, Alastair C Keen, Caroline Rauffenbart, Jacqueline Glenn, Steven J Charlton, Silvia Lovera, Zara A Sands, Ali Ates, Martyn Wood, Meritxell Canals, Jonathan A Javitch, Jens Carlsson, J Robert Lane

{"title":"Identification of a Lipid-Exposed Extrahelical Binding Site for Positive Allosteric Modulators of the Dopamine D2 Receptor.","authors":"Herman D Lim, Damian Bartuzi, Alastair C Keen, Caroline Rauffenbart, Jacqueline Glenn, Steven J Charlton, Silvia Lovera, Zara A Sands, Ali Ates, Martyn Wood, Meritxell Canals, Jonathan A Javitch, Jens Carlsson, J Robert Lane","doi":"10.1021/acschemneuro.5c00105","DOIUrl":"10.1021/acschemneuro.5c00105","url":null,"abstract":"Recently, the first small-molecule positive allosteric modulators (PAMs) of the dopamine D2 receptor (D2R) were identified. The more potent PAM potentiated the effects of D2R signaling in vitro and in an in vivo model predictive of anti-Parkinson's efficacy. We reveal, based on the results of our site-directed mutagenesis and molecular dynamics experiments, that this scaffold binds to a hitherto unexploited lipid-exposed extrahelical allosteric site in the D2R that lies in a cleft toward the intracellular aspect of the D2R defined by residues in transmembrane domains 1 and 7 and helix 8. By binding to this site, the PAM acts to potentiate the binding affinity of efficacious agonists, such as dopamine. Our simulations suggest that the PAM achieves this effect by stabilizing an active-like conformation of the receptor, similar to the G protein-bound state with TM5 and the tyrosine toggle switch playing the major role.","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":"2295-2311"},"PeriodicalIF":4.1,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12186844/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144074841","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Correction to "Differential Effects of Aβ Peptides on the Plasmin-Dependent Degradation of ApoE3 and ApoE4". 修正了“Aβ肽对纤溶蛋白依赖性降解ApoE3和ApoE4的差异影响”。

IF 4.1 3区医学

ACS Chemical Neuroscience Pub Date : 2025-06-18 Epub Date: 2025-06-02 DOI: 10.1021/acschemneuro.5c00324

Merc M Kemeh, Anthony J Furnelli, Noel D Lazo

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Tyrosine: A Key Neurotransmitter in Selective Serotonin Reuptake Inhibitor Treatment for Chronic Restraint Stress-Induced Reduction of Intestinal Innate Lymphoid Cell Type 3 Cells. 酪氨酸：选择性血清素再摄取抑制剂治疗慢性约束应激诱导肠道先天淋巴样细胞3型细胞减少的关键神经递质。

IF 4.1 3区医学

ACS Chemical Neuroscience Pub Date : 2025-06-18 Epub Date: 2025-06-04 DOI: 10.1021/acschemneuro.5c00271

Yilin Wu, Chujun Duan, Niqi Shan, Yuling Wang, Shanshou Liu, Linxiao Wang, Yangmengjie Jing, Hanyin Fan, Jinyue Yang, Yuan Zhang, Lin Liu, Ran Zhuang

{"title":"Tyrosine: A Key Neurotransmitter in Selective Serotonin Reuptake Inhibitor Treatment for Chronic Restraint Stress-Induced Reduction of Intestinal Innate Lymphoid Cell Type 3 Cells.","authors":"Yilin Wu, Chujun Duan, Niqi Shan, Yuling Wang, Shanshou Liu, Linxiao Wang, Yangmengjie Jing, Hanyin Fan, Jinyue Yang, Yuan Zhang, Lin Liu, Ran Zhuang","doi":"10.1021/acschemneuro.5c00271","DOIUrl":"10.1021/acschemneuro.5c00271","url":null,"abstract":"Selective serotonin reuptake inhibitors (SSRIs) are widely used antidepressants. Given the prevalence of depression and its associated immune dysregulation, understanding the role of SSRIs in these processes is crucial. This study aims to explore the effects of SSRIs on chronic restraint stress (CRS)-induced depressive-like behaviors and immune functions. Mice subjected to CRS were administered citalopram (CITA) during the modeling period, followed by behavioral assessments. Histological examination and flow cytometry were used to analyze the immune status and cells of the spleen and intestine. Cellular experiments were performed for verification. We found that CITA treatment significantly alleviated weight loss and depression-like behaviors in CRS mice. Moreover, CITA ameliorated CRS-induced immune dysregulation in the spleen and reversed the decreased villus/crypt ratio in the ileum. Although CITA had minimal impact on restoring intraepithelial lymphocytes after CRS, it significantly reversed the reduction in innate lymphoid cell type 3 (ILC3) levels. Notably, although levels of the serotonin precursor 5-hydroxytryptophan remained unchanged in the ileum, tyrosine levels significantly increased after CRS and were further reduced by CITA treatment. Treatment of primary ILC3s with 4-ethylphenol, a tyrosine metabolite, decreased ILC3 cells and their related IL-7 levels, suggesting that tyrosine may be a key neurotransmitter regulating ILC3 levels through CITA. Hence, CITA effectively ameliorates CRS-induced depressive-like behaviors and immune dysfunctions in the spleen and intestine. Tyrosine is a crucial neurotransmitter in CITA treatment for regulating depression-related intestinal immune disorders.","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":"2312-2321"},"PeriodicalIF":4.1,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144223701","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}

引用次数: 0

IF 4.1 3区医学

ACS Chemical Neuroscience Pub Date : 2025-06-18

Yi-Yue Zhang, Rui-Feng Li, Jing Tian, Jun Peng* and Xiu-Ju Luo*,

引用次数: 0

IF 4.1 3区医学

ACS Chemical Neuroscience Pub Date : 2025-06-18

Prabir Kumar Gharai, Juhee Khan, Rathnam Mallesh, Shubham Garg, Sanju Gupta, Parasuraman Jaisankar and Surajit Ghosh*,

引用次数: 0

IF 4.1 3区医学

ACS Chemical Neuroscience Pub Date : 2025-06-18

Herman D. Lim, Damian Bartuzi, Alastair C Keen, Caroline Rauffenbart, Jacqueline Glenn, Steven J. Charlton, Silvia Lovera, Zara A. Sands, Ali Ates, Martyn Wood, Meritxell Canals, Jonathan A. Javitch, Jens Carlsson* and J. Robert Lane*,

引用次数: 0

Dl-3-n-Butylphthalide Alleviates Cognitive Impairment in Chronic Cerebral Hypoperfusion: Associations with Mitochondrial Permeability Transition Pore Closure and Suppression of Excessive Mitophagy. dl -3-n-丁苯酞减轻慢性脑灌注不足的认知障碍：与线粒体通透性过渡孔关闭和过度线粒体自噬的抑制有关。

IF 4.1 3区医学

ACS Chemical Neuroscience Pub Date : 2025-06-18 Epub Date: 2025-05-29 DOI: 10.1021/acschemneuro.4c00826

Yaqiong Li, Junkui Shang, Huiwen Zhang, Yaru Lu, Ying Zhao, Yadan Wang, Xi Yan, Jiewen Zhang

{"title":"Dl-3-n-Butylphthalide Alleviates Cognitive Impairment in Chronic Cerebral Hypoperfusion: Associations with Mitochondrial Permeability Transition Pore Closure and Suppression of Excessive Mitophagy.","authors":"Yaqiong Li, Junkui Shang, Huiwen Zhang, Yaru Lu, Ying Zhao, Yadan Wang, Xi Yan, Jiewen Zhang","doi":"10.1021/acschemneuro.4c00826","DOIUrl":"10.1021/acschemneuro.4c00826","url":null,"abstract":"Chronic cerebral hypoperfusion (CCH) results in cognitive impairment, with mitochondrial dysfunction identified as a key contributor. The opening of the mitochondrial permeability transition pore (mPTP) is closely associated with mitochondrial dysfunction and excessive mitophagy, particularly under stress conditions. Dl-3-n-Butylphthalide (Dl-NBP) has been shown to ameliorate cognitive impairment caused by CCH. However, whether Dl-NBP exerts its effects by inhibiting mPTP opening and mitigating excessive mitophagy remains unclear. In this study, we established a rat model of CCH through permanent bilateral common carotid artery occlusion (BCCAO) and explored the neuroprotective effects of Dl-NBP and its underlying mechanisms. The neuroprotective effects of Dl-NBP were evaluated using the Morris water maze test, and protein expression levels related to mPTP, apoptosis, and mitophagy were assessed through Western blotting and immunofluorescence. The ultrastructural changes in mitochondrial morphology and mitophagosomes were observed using transmission electron microscopy. We found that CCH led to cognitive impairment in rats, along with increased expression of p53, cytochrome-c, cleaved-Caspase3, LC3II/LC3I, Beclin1, P62, PINK1, and Parkin in the hippocampal tissue. Additionally, CCH caused an accumulation of mitophagosomes in the hippocampal tissue, although it did not affect Cyclophilin D (CypD) expression levels. However, Dl-NBP reversed these changes, except for CypD. Taken together, these findings suggest that Dl-NBP may improve cognitive impairment in CCH rats, potentially through the reduction of hippocampal neuron apoptosis by inhibiting mPTP opening and excessive mitophagy. Dl-NBP may represent a potential therapeutic strategy for treating cognitive impairment associated with CCH.","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":"2208-2216"},"PeriodicalIF":4.1,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12183690/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144179757","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Prediction of Specificity of α-Conotoxins to Subtypes of Human Nicotinic Acetylcholine Receptors with Semi-supervised Machine Learning. 半监督机器学习预测α-Conotoxins对人类烟碱乙酰胆碱受体亚型的特异性

IF 4.1 3区医学

ACS Chemical Neuroscience Pub Date : 2025-06-18 Epub Date: 2025-05-29 DOI: 10.1021/acschemneuro.4c00760

Hung Nguyen Do, Jessica Z Kubicek-Sutherland, Sandrasegaram Gnanakaran

{"title":"Prediction of Specificity of α-Conotoxins to Subtypes of Human Nicotinic Acetylcholine Receptors with Semi-supervised Machine Learning.","authors":"Hung Nguyen Do, Jessica Z Kubicek-Sutherland, Sandrasegaram Gnanakaran","doi":"10.1021/acschemneuro.4c00760","DOIUrl":"10.1021/acschemneuro.4c00760","url":null,"abstract":"Conotoxins are a family of highly toxic neurotoxins composed of cysteine-rich peptides produced by marine cone snails. The most lethal cone snail species to humans is Conus geographus, with fatality rates of up to ∼65% from a single sting, which is caused mostly by the activity of α-conotoxins against human nicotinic acetylcholine receptors (nAChRs). While sequence-based machine learning (ML) classifiers have been trained to identify targets of conotoxins binding voltage-gated ion channels, no ML model has been built to predict the subtype-specific nAChR targets of α-conotoxins. Here, we trained an ML model in a semi-supervised manner to predict the specificity of α-conotoxin binding toward different human nAChR subtypes to overcome the challenge of limited data in subtype-specific nAChR targets of α-conotoxins and the issue that one α-conotoxin can bind multiple nAChR subtypes with high selectivity. We considered additional features of sequences of α-conotoxins in training our ML model, including the secondary structure propensities and electrostatic properties, which resulted in better prediction capability for the ML model. Notably, we identify that most α-conotoxins bind to α3β2, α1γδ, and α7 subtypes of human nAChRs. Our findings from this study provide a framework for predicting targets of various kinds of toxins.","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":"2196-2207"},"PeriodicalIF":4.1,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12183688/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144179840","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

IF 4.1 3区医学

ACS Chemical Neuroscience Pub Date : 2025-06-18

Merc M. Kemeh, Anthony J. Furnelli and Noel D. Lazo*,

引用次数: 0

IF 4.1 3区医学

ACS Chemical Neuroscience Pub Date : 2025-06-18

Kalpana Pandya, Krishnashish Roul, Avanish Tripathi, Sateesh Belemkar, Anshuman Sinha, Meryem Erol and Devendra Kumar*,

引用次数: 0