Journal of General Physiology最新文献_第3页

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":"https://doi.org/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

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

PANX1 hexamers work but cells prefer heptamers. PANX1 六聚体可以工作，但细胞更喜欢七聚体。

IF 3.3 2区医学

Journal of General Physiology Pub Date : 2025-03-03 Epub Date: 2025-02-05 DOI: 10.1085/jgp.202413727

Andrew L Harris

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

ERG responses to high-frequency flickers require FAT3 signaling in mouse retinal bipolar cells. 小鼠视网膜双极细胞对高频闪烁的ERG反应需要FAT3信号。

IF 3.3 2区医学

Journal of General Physiology Pub Date : 2025-03-03 Epub Date: 2025-02-04 DOI: 10.1085/jgp.202413642

Evelyn C Avilés, Sean K Wang, Sarina Patel, Sebastian Cordero, Shuxiang Shi, Lucas Lin, Vladimir J Kefalov, Lisa V Goodrich, Constance L Cepko, Yunlu Xue

{"title":"ERG responses to high-frequency flickers require FAT3 signaling in mouse retinal bipolar cells.","authors":"Evelyn C Avilés, Sean K Wang, Sarina Patel, Sebastian Cordero, Shuxiang Shi, Lucas Lin, Vladimir J Kefalov, Lisa V Goodrich, Constance L Cepko, Yunlu Xue","doi":"10.1085/jgp.202413642","DOIUrl":"10.1085/jgp.202413642","url":null,"abstract":"Vision is initiated by the reception of light by photoreceptors and subsequent processing via downstream retinal neurons. Proper circuit organization depends on the multifunctional tissue polarity protein FAT3, which is required for amacrine cell connectivity and retinal lamination. Here, we investigated the retinal function of Fat3 mutant mice and found decreases in both electroretinography and perceptual responses to high-frequency flashes. These defects did not correlate with abnormal amacrine cell wiring, pointing instead to a role in bipolar cell subtypes that also express FAT3. The role of FAT3 in the response to high temporal frequency flashes depends upon its ability to transduce an intracellular signal. Mechanistically, FAT3 binds to the synaptic protein PTPσ intracellularly and is required to localize GRIK1 to OFF-cone bipolar cell synapses with cone photoreceptors. These findings expand the repertoire of FAT3's functions and reveal its importance in bipolar cells for high-frequency light response.","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/PMC11793021/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143191022","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

Modeling the effects of thin filament near-neighbor cooperative interactions in mammalian myocardium. 哺乳动物心肌中细丝近邻合作相互作用的模拟。

IF 3.3 2区医学

Journal of General Physiology Pub Date : 2025-03-03 Epub Date: 2025-01-27 DOI: 10.1085/jgp.202413582

Tuan A Phan, Daniel P Fitzsimons

{"title":"Modeling the effects of thin filament near-neighbor cooperative interactions in mammalian myocardium.","authors":"Tuan A Phan, Daniel P Fitzsimons","doi":"10.1085/jgp.202413582","DOIUrl":"10.1085/jgp.202413582","url":null,"abstract":"The mechanisms underlying cooperative activation and inactivation of myocardial force extend from local, near-neighbor interactions involving troponin-tropomyosin regulatory units (RU) and crossbridges (XB) to more global interactions across the sarcomere. To better understand these mechanisms in the hearts of small and large mammals, we undertook a simplified mathematical approach to assess the contribution of three types of near-neighbor cooperative interactions, i.e., RU-induced, RU-activation (RU-RU), crossbridge-induced, crossbridge-binding (XB-XB), and XB-induced, RU-activation (XB-RU). We measured the Ca2+ and activation dependence of the rate constant of force redevelopment in murine- and porcine-permeabilized ventricular myocardium. Mathematical modeling of these three near-neighbor interactions yielded nonlinear expressions for the RU-RU and XB-RU rate coefficients (kon and koff) and XB-XB rate coefficients describing the attachment of force-generating crossbridges (f and f'). The derivation of single cooperative coefficient parameters (u = RU-RU, w = XB-RU, and v = XB-XB) permitted an initial assessment of the strength of each near-neighbor interaction. The parameter sets describing the effects of discrete XB-XB or XB-RU interactions failed to adequately fit the in vitro contractility data in either murine or porcine myocardium. However, the Ca2+ dependence of ktr in murine and porcine ventricular myocardium was well fit by parameter sets incorporating the RU-RU cooperative interaction. Our results indicate that a significantly stronger RU-RU interaction is present in porcine ventricular myocardium compared with murine ventricular myocardium and that the relative strength of the near-neighbor RU-RU interaction contributes to species-specific myocardial contractile dynamics in small and large mammals.","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/PMC11771317/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143048773","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

Drugs exhibit diverse binding modes and access routes in the Nav1.5 cardiac sodium channel pore. 药物在Nav1.5心脏钠通道孔中表现出不同的结合模式和通路。

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.202413658

Elaine Tao, Ben Corry

{"title":"Drugs exhibit diverse binding modes and access routes in the Nav1.5 cardiac sodium channel pore.","authors":"Elaine Tao, Ben Corry","doi":"10.1085/jgp.202413658","DOIUrl":"10.1085/jgp.202413658","url":null,"abstract":"Small molecule inhibitors of the sodium channel are common pharmacological agents used to treat a variety of cardiac and nervous system pathologies. They act on the channel via binding within the pore to directly block the sodium conduction pathway and/or modulate the channel to favor a non-conductive state. Despite their abundant clinical use, we lack specific knowledge of their protein-drug interactions and the subtle variations between different compound structures. This study investigates the binding and accessibility of nine different compounds in the pore cavity of the Nav1.5 sodium channel using enhanced sampling simulations. We find that most compounds share a common location of pore binding-near the mouth of the DII-III fenestration-associated with the high number of aromatic residues in this region. In contrast, some other compounds prefer binding within the lateral fenestrations where they compete with lipids, rather than binding in the central cavity. Overall, our simulation results suggest that the drug binding within the pore is highly promiscuous, with most drugs having multiple low-affinity binding sites. Access to the pore interior via two out of four of the hydrophobic fenestrations is favorable for the majority of compounds. Our results indicate that the polyspecific and diffuse binding of inhibitors in the pore contributes to the varied nature of their inhibitory effects and can be exploited for future drug discovery and optimization.","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/PMC11706274/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142959010","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

Correction: How could simulations elucidate Nav1.5 channel blockers mechanism? 更正：模拟如何阐明Nav1.5通道阻滞剂机制？

IF 3.3 2区医学

Journal of General Physiology Pub Date : 2025-02-03 Epub Date: 2025-01-16 DOI: 10.1085/jgp.20241373001082025c

Tanadet Pipatpolkai

引用次数: 0

Distinct properties and activation of hexameric and heptameric Pannexin 1 channel concatemers. 六聚体和七聚体Pannexin 1通道连接物的不同性质和活化。

IF 3.3 2区医学

Journal of General Physiology Pub Date : 2025-01-06 Epub Date: 2024-12-20 DOI: 10.1085/jgp.202413676

Smriti Gupta, Yu-Hsin Chiu, Mohan C Manjegowda, Bimal N Desai, Kodi S Ravichandran, Douglas A Bayliss

{"title":"Distinct properties and activation of hexameric and heptameric Pannexin 1 channel concatemers.","authors":"Smriti Gupta, Yu-Hsin Chiu, Mohan C Manjegowda, Bimal N Desai, Kodi S Ravichandran, Douglas A Bayliss","doi":"10.1085/jgp.202413676","DOIUrl":"10.1085/jgp.202413676","url":null,"abstract":"Pannexin 1 (PANX1) is a member of a topologically related and stoichiometrically diverse family of large pore membrane ion channels that support the flux of signaling metabolites (e.g., ATP) and fluorescent dyes. High-resolution structural analyses have identified PANX1 as a heptamer despite early evidence suggesting that it might be a hexamer. To determine if PANX1 channel activity is supported in both hexameric and heptameric conformations, we examined properties of concatenated PANX1 constructs comprising either six or seven subunits with intact or truncated C-termini (the latter to mimic caspase-cleavage activation). In whole-cell recordings from PANX1-deleted cells, the C-tail-truncated hexameric and heptameric concatemers generated outwardly rectifying PANX1-like currents only after severing the intersubunit linkers. Surprisingly, α1D adrenoceptor stimulation activated constructs with intact or truncated C-tails, even without linker cleavage. In inside-out patches from PANX1-deleted cells, linker cleavage activated C-tail truncated channels derived from either hexameric or heptameric concatemers. The heptamers presented peak unitary conductance and mean open time that was similar to channels assembled from the expression of unlinked single PANX1 subunits and greater than from the hexamers. In addition, the linker-cleaved heptameric concatemers supported greater PANX1-dependent ATP release and TO-PRO-3 uptake than the corresponding hexamers. These data indicate that functional PANX1 channels can be obtained in either hexameric or heptameric conformations and suggest that the distinct unitary properties of heptameric channels are more conducive to large molecule permeation by PANX1; they also suggest that there are distinct structural requirements for C-tail cleavage and receptor-mediated PANX1 activation mechanisms.","PeriodicalId":54828,"journal":{"name":"Journal of General Physiology","volume":"157 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11666100/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142866481","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

A misstep in the multistep process of fast inactivation. 多步骤快速失活过程中的一个失误。

IF 3.3 2区医学

Journal of General Physiology Pub Date : 2025-01-06 Epub Date: 2024-12-17 DOI: 10.1085/jgp.202413735

Ben Short

引用次数: 0