Journal of General Physiology最新文献_第3页

Modeling cardiac contractile cooperativity across species. 跨物种心脏收缩协同性建模。

IF 3.3 2区医学

Journal of General Physiology Pub Date : 2025-03-03 Epub Date: 2025-01-31 DOI: 10.1085/jgp.202413722

Matthew Carter Childers

引用次数: 0

FAT3 provides a flicker of light. FAT3提供了一个闪烁的光。

IF 3.3 2区医学

Journal of General Physiology Pub Date : 2025-03-03 Epub Date: 2025-02-11 DOI: 10.1085/jgp.202513772

Ben Short

引用次数: 0

Reduced voltage-activated Ca2+ release flux in muscle fibers from a rat model of Duchenne dystrophy. 降低电压激活的Ca2+释放通量从大鼠杜氏营养不良模型的肌肉纤维。

IF 3.3 2区医学

Journal of General Physiology Pub Date : 2025-03-03 Epub Date: 2024-12-24 DOI: 10.1085/jgp.202413588

Jonathan Schreiber, Ludivine Rotard, Yves Tourneur, Aude Lafoux, Christine Berthier, Bruno Allard, Corinne Huchet, Vincent Jacquemond

{"title":"Reduced voltage-activated Ca2+ release flux in muscle fibers from a rat model of Duchenne dystrophy.","authors":"Jonathan Schreiber, Ludivine Rotard, Yves Tourneur, Aude Lafoux, Christine Berthier, Bruno Allard, Corinne Huchet, Vincent Jacquemond","doi":"10.1085/jgp.202413588","DOIUrl":"10.1085/jgp.202413588","url":null,"abstract":"The potential pathogenic role of disturbed Ca2+ homeostasis in Duchenne muscular dystrophy (DMD) remains a complex, unsettled issue. We used muscle fibers isolated from 3-mo-old DMDmdx rats to further investigate the case. Most DMDmdx fibers exhibited no sign of trophic or morphology distinction as compared with WT fibers and mitochondria and t-tubule membrane networks also showed no stringent discrepancy. Under voltage clamp, values for holding current were similar in the two groups, whereas values for capacitance were larger in DMDmdx fibers, suggestive of enhanced amount of t-tubule membrane. The Ca2+ current density across the channel carried by the EC coupling voltage sensor (CaV1.1) was unchanged. The maximum rate of voltage-activated sarcoplasmic reticulum (SR) Ca2+ release was reduced by 25% in the DMDmdx fibers, with no change in voltage dependency. Imaging resting Ca2+ revealed rare spontaneous local SR Ca2+ release events with no sign of elevated activity in DMDmdx fibers. Under current clamp, DMDmdx fibers generated similar trains of action potentials as WT fibers. Results suggest that reduced peak amplitude of SR Ca2+ release is an inherent feature of this DMD model, likely contributing to muscle weakness. This occurs despite a preserved amount of releasable Ca2+ and with no change in excitability, CaV1.1 channel activity, and SR Ca2+ release at rest. Although we cannot exclude that fibers from the 3-mo-old animals do not yet display a fully developed disease phenotype, results provide limited support for pathomechanistic concepts frequently associated with DMD such as membrane fragility, excessive Ca2+ entry, or enhanced SR Ca2+ leak.","PeriodicalId":54828,"journal":{"name":"Journal of General Physiology","volume":"157 2","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11668172/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142883090","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

ALLIN: A tool for annotation of a protein alignment combined with structural visualization. ALLIN：一个结合结构可视化的蛋白质排列注释工具。

IF 3.3 2区医学

Journal of General Physiology Pub Date : 2025-03-03 Epub Date: 2024-12-31 DOI: 10.1085/jgp.202413635

Alessandra Picollo, Michael Pusch

{"title":"ALLIN: A tool for annotation of a protein alignment combined with structural visualization.","authors":"Alessandra Picollo, Michael Pusch","doi":"10.1085/jgp.202413635","DOIUrl":"10.1085/jgp.202413635","url":null,"abstract":"The physiological, functional, and structural properties of proteins and their pathogenic variants can be summarized using many tools. The information relating to a single protein is often spread among different sources requiring different programs for access. It is not always easy to select, simultaneously visualize, and compare specific properties of different proteins. On the other hand, comparing members of the same protein family could suggest conserved properties or highlight significant differences. We have thus developed a web interface, ALLIN (Annotation of sequence aLignment and structuraL proteIn visualizatioN) for the simultaneous visualization of multi-sequence protein alignments, including comments and annotations, and the related three-dimensional structures. This interface permits the inclusion of comments and coloring of residues in the alignment section, according to a user-defined color code, allowing a quick overview of specific properties. The interface does not require training or coding expertise, and the result is a unique \"memo\" web page that combines data from different sources, with the flexibility to highlight only the information of interest. The output provides an overview of the state of art of a protein family that is easily shared among researchers and new data can be conveniently added as it emerges. We believe the ALLIN tool can be useful for all scientists working on the structure-function analysis of proteins, in particular on those involved in human genetic diseases.","PeriodicalId":54828,"journal":{"name":"Journal of General Physiology","volume":"157 2","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11687298/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142907709","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Inactivation of CaV1 and CaV2 channels. CaV1和CaV2通道失活。

IF 3.3 2区医学

Journal of General Physiology Pub Date : 2025-03-03 Epub Date: 2025-01-30 DOI: 10.1085/jgp.202313531

Worawan B Limpitikul, Ivy E Dick

引用次数: 0

Nociceptor sodium channels shape subthreshold phase, upstroke, and shoulder of action potentials. 痛觉感受器钠通道形成动作电位的阈下相、上冲程和肩部。

IF 3.3 2区医学

Journal of General Physiology Pub Date : 2025-03-03 Epub Date: 2025-01-21 DOI: 10.1085/jgp.202313526

Phil Alexander Köster, Enrico Leipold, Jenny Tigerholm, Anna Maxion, Barbara Namer, Thomas Stiehl, Angelika Lampert

{"title":"Nociceptor sodium channels shape subthreshold phase, upstroke, and shoulder of action potentials.","authors":"Phil Alexander Köster, Enrico Leipold, Jenny Tigerholm, Anna Maxion, Barbara Namer, Thomas Stiehl, Angelika Lampert","doi":"10.1085/jgp.202313526","DOIUrl":"10.1085/jgp.202313526","url":null,"abstract":"Voltage-gated sodium channels (VGSCs) in the peripheral nervous system shape action potentials (APs) and thereby support the detection of sensory stimuli. Most of the nine mammalian VGSC subtypes are expressed in nociceptors, but predominantly, three are linked to several human pain syndromes: while Nav1.7 is suggested to be a (sub-)threshold channel, Nav1.8 is thought to support the fast AP upstroke. Nav1.9, as it produces large persistent currents, is attributed a role in determining the resting membrane potential. We characterized the gating of Nav1.1-Nav1.3 and Nav1.5-Nav1.9 in manual patch clamp with a focus on the AP subthreshold depolarization phase. Nav1.9 exhibited the most hyperpolarized activation, while its fast inactivation resembled the depolarized inactivation of Nav1.8. For some VGSCs (e.g., Nav1.1 and Nav1.2), a positive correlation between ramp current and window current was detected. Using a modified Hodgkin-Huxley model that accounts for the time needed for inactivation to occur, we used the acquired data to simulate two nociceptive nerve fiber types (an Aδ- and a mechano-insensitive C-nociceptor) containing VGSC conductances according to published human RNAseq data. Our simulations suggest that Nav1.9 is supporting both the AP upstroke and its shoulder. A reduced threshold for AP generation was induced by enhancing Nav1.7 conductivity or shifting its activation to more hyperpolarized potentials, as observed in Nav1.7-related pain disorders. Here, we provide a comprehensive, comparative functional characterization of VGSCs relevant in nociception and describe their gating with Hodgkin-Huxley-like models, which can serve as a tool to study their specific contributions to AP shape and sodium channel-related diseases.","PeriodicalId":54828,"journal":{"name":"Journal of General Physiology","volume":"157 2","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11748974/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143016692","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

How could simulations elucidate Nav1.5 channel blockers mechanism? 模拟如何阐明Nav1.5通道阻滞剂的机制？

IF 3.3 2区医学

Journal of General Physiology Pub Date : 2025-03-03 Epub Date: 2025-01-07 DOI: 10.1085/jgp.202413730

Tanadet Pipatpolkai

引用次数: 0

JGP in 2025. 2025年JGP。

IF 3.3 2区医学

Journal of General Physiology Pub Date : 2025-03-03 Epub Date: 2025-02-03 DOI: 10.1085/jgp.202513758

David Eisner

引用次数: 0

Structural and functional insights into α-actinin isoforms and their implications in cardiovascular disease. α-肌动蛋白异构体的结构和功能及其在心血管疾病中的意义。

IF 3.3 2区医学

Journal of General Physiology Pub Date : 2025-03-03 Epub Date: 2025-02-07 DOI: 10.1085/jgp.202413684

Maya Noureddine, Halina Mikolajek, Neil V Morgan, Chris Denning, Siobhan Loughna, Katja Gehmlich, Fiyaz Mohammed

{"title":"Structural and functional insights into α-actinin isoforms and their implications in cardiovascular disease.","authors":"Maya Noureddine, Halina Mikolajek, Neil V Morgan, Chris Denning, Siobhan Loughna, Katja Gehmlich, Fiyaz Mohammed","doi":"10.1085/jgp.202413684","DOIUrl":"10.1085/jgp.202413684","url":null,"abstract":"α-actinin (ACTN) is a pivotal member of the actin-binding protein family, crucial for the anchoring and organization of actin filaments within the cytoskeleton. Four isoforms of α-actinin exist: two non-muscle isoforms (ACTN1 and ACTN4) primarily associated with actin stress fibers and focal adhesions, and two muscle-specific isoforms (ACTN2 and ACTN3) localized to the Z-disk of the striated muscle. Although these isoforms share structural similarities, they exhibit distinct functional characteristics that reflect their specialized roles in various tissues. Genetic variants in α-actinin isoforms have been implicated in a range of pathologies, including cardiomyopathies, thrombocytopenia, and non-cardiovascular diseases, such as nephropathy. However, the precise impact of these genetic variants on the α-actinin structure and their contribution to disease pathogenesis remains poorly understood. This review provides a comprehensive overview of the structural and functional attributes of the four α-actinin isoforms, emphasizing their roles in actin crosslinking and sarcomere stabilization. Furthermore, we present detailed structural modeling of select ACTN1 and ACTN2 variants to elucidate mechanisms underlying disease pathogenesis, with a particular focus on macrothrombocytopenia and hypertrophic cardiomyopathy. By advancing our understanding of α-actinin's role in both normal cellular function and disease states, this review lays the groundwork for future research and the development of targeted therapeutic interventions.","PeriodicalId":54828,"journal":{"name":"Journal of General Physiology","volume":"157 2","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11804879/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143366550","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

The differential impacts of equivalent gating-charge mutations in voltage-gated sodium channels. 电压门控钠通道中等效门控电荷突变的差异影响。

IF 3.3 2区医学

Journal of General Physiology Pub Date : 2025-03-03 Epub Date: 2025-01-17 DOI: 10.1085/jgp.202413669

Eslam Elhanafy, Amin Akbari Ahangar, Rebecca Roth, Tamer M Gamal El-Din, John R Bankston, Jing Li

{"title":"The differential impacts of equivalent gating-charge mutations in voltage-gated sodium channels.","authors":"Eslam Elhanafy, Amin Akbari Ahangar, Rebecca Roth, Tamer M Gamal El-Din, John R Bankston, Jing Li","doi":"10.1085/jgp.202413669","DOIUrl":"10.1085/jgp.202413669","url":null,"abstract":"Voltage-gated sodium (Nav) channels are pivotal for cellular signaling, and mutations in Nav channels can lead to excitability disorders in cardiac, muscular, and neural tissues. A major cluster of pathological mutations localizes in the voltage-sensing domains (VSDs), resulting in either gain-of-function, loss-of-function effects, or both. However, the mechanism behind this functional diversity of mutations at equivalent positions remains elusive. Through hotspot analysis, we identified three gating charges (R1, R2, and R3) as major mutational hotspots in VSDs. The same amino acid substitutions at equivalent gating-charge positions in VSDI and VSDII of the cardiac sodium channel Nav1.5 show differential gating property impacts in electrophysiology measurements. We conducted molecular dynamics (MD) simulations on wild-type channels and six mutants to elucidate the structural basis of their differential impacts. Our 120-µs MD simulations with applied external electric fields captured VSD state transitions and revealed the differential structural dynamics between equivalent R-to-Q mutants. Notably, we observed transient leaky conformations in some mutants during structural transitions, offering a detailed structural explanation for gating-pore currents. Our salt-bridge network analysis uncovered VSD-specific and state-dependent interactions among gating charges, countercharges, and lipids. This detailed analysis revealed how mutations disrupt critical electrostatic interactions, thereby altering VSD permeability and modulating gating properties. By demonstrating the crucial importance of considering the specific structural context of each mutation, our study advances our understanding of structure-function relationships in Nav channels. Our work establishes a robust framework for future investigations into the molecular basis of ion channel-related disorders.","PeriodicalId":54828,"journal":{"name":"Journal of General Physiology","volume":"157 2","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11740781/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143015717","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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