Journal of General Physiology最新文献

Exercise training may reduce fragmented mitochondria in the ischemic-reperfused heart through DRP1. 运动训练可通过 DRP1 减少缺血再灌注心脏中的线粒体碎片。

IF 4.3 2区医学

Journal of General Physiology Pub Date : 2024-12-02 Epub Date: 2024-11-07 DOI: 10.1085/jgp.202313485

Mathilde Dubois, Florian Pallot, Maxime Gouin-Gravezat, Doria Boulghobra, Florence Coste, Guillaume Walther, Gregory Meyer, Isabelle Bornard, Cyril Reboul

引用次数: 0

Stochastic force generation in an isometric binary mechanical system. 等距二元机械系统中的随机力产生。

IF 3.3 2区医学

Journal of General Physiology Pub Date : 2024-12-02 Epub Date: 2024-11-19 DOI: 10.1085/jgp.202313493

Vidya Murthy, Josh E Baker

{"title":"Stochastic force generation in an isometric binary mechanical system.","authors":"Vidya Murthy, Josh E Baker","doi":"10.1085/jgp.202313493","DOIUrl":"10.1085/jgp.202313493","url":null,"abstract":"Accurate models of muscle contraction are necessary for understanding muscle performance and the molecular modifications that enhance it (e.g., therapeutics, posttranslational modifications, etc.). As a thermal system containing millions of randomly fluctuating atoms that on the thermal scale of a muscle fiber generate unidirectional force and power output, muscle mechanics are constrained by the laws of thermodynamics. According to a thermodynamic muscle model, muscle's power stroke occurs with the shortening of an entropic spring consisting of an ensemble of force-generating myosin motor switches, each induced by actin binding and gated by inorganic phosphate release. This model differs fundamentally from conventional molecular power stroke models that assign springs to myosin motors in that it is physically impossible to describe an entropic spring in terms of the springs of its molecular constituents. A simple two-state thermodynamic model (a binary mechanical system) accurately accounts for muscle force-velocity relationships, force transients following rapid mechanical and chemical perturbations, and a thermodynamic work loop. Because this model transforms our understanding of muscle contraction, it must continue to be tested. Here, we show that a simple stochastic kinetic simulation of isometric muscle force predicts four phases of a force-generating loop that bifurcates between periodic and stochastic beating through mechanisms framed by two thermodynamic equations. We compare these model predictions with experimental data including observations of spontaneous oscillatory contractions (SPOCs) in muscles and periodic force generation in small myosin ensembles.","PeriodicalId":54828,"journal":{"name":"Journal of General Physiology","volume":"156 12","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142669570","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Functional role of myosin-binding protein H in thick filaments of developing vertebrate fast-twitch skeletal muscle. 肌球蛋白结合蛋白 H 在发育中脊椎动物快节奏骨骼肌粗丝中的功能作用

IF 3.3 2区医学

Journal of General Physiology Pub Date : 2024-12-02 Epub Date: 2024-10-07 DOI: 10.1085/jgp.202413604

Andrew F Mead, Neil B Wood, Shane R Nelson, Bradley M Palmer, Lin Yang, Samantha Beck Previs, Angela Ploysangngam, Guy G Kennedy, Jennifer F McAdow, Sarah M Tremble, Marcus A Zimmermann, Marilyn J Cipolla, Alicia M Ebert, Aaron N Johnson, Christina A Gurnett, Michael J Previs, David M Warshaw

{"title":"Functional role of myosin-binding protein H in thick filaments of developing vertebrate fast-twitch skeletal muscle.","authors":"Andrew F Mead, Neil B Wood, Shane R Nelson, Bradley M Palmer, Lin Yang, Samantha Beck Previs, Angela Ploysangngam, Guy G Kennedy, Jennifer F McAdow, Sarah M Tremble, Marcus A Zimmermann, Marilyn J Cipolla, Alicia M Ebert, Aaron N Johnson, Christina A Gurnett, Michael J Previs, David M Warshaw","doi":"10.1085/jgp.202413604","DOIUrl":"10.1085/jgp.202413604","url":null,"abstract":"Myosin-binding protein H (MyBP-H) is a component of the vertebrate skeletal muscle sarcomere with sequence and domain homology to myosin-binding protein C (MyBP-C). Whereas skeletal muscle isoforms of MyBP-C (fMyBP-C, sMyBP-C) modulate muscle contractility via interactions with actin thin filaments and myosin motors within the muscle sarcomere \"C-zone,\" MyBP-H has no known function. This is in part due to MyBP-H having limited expression in adult fast-twitch muscle and no known involvement in muscle disease. Quantitative proteomics reported here reveal that MyBP-H is highly expressed in prenatal rat fast-twitch muscles and larval zebrafish, suggesting a conserved role in muscle development and prompting studies to define its function. We take advantage of the genetic control of the zebrafish model and a combination of structural, functional, and biophysical techniques to interrogate the role of MyBP-H. Transgenic, FLAG-tagged MyBP-H or fMyBP-C both localize to the C-zones in larval myofibers, whereas genetic depletion of endogenous MyBP-H or fMyBP-C leads to increased accumulation of the other, suggesting competition for C-zone binding sites. Does MyBP-H modulate contractility in the C-zone? Globular domains critical to MyBP-C's modulatory functions are absent from MyBP-H, suggesting that MyBP-H may be functionally silent. However, our results suggest an active role. In vitro motility experiments indicate MyBP-H shares MyBP-C's capacity as a molecular \"brake.\" These results provide new insights and raise questions about the role of the C-zone during muscle development.","PeriodicalId":54828,"journal":{"name":"Journal of General Physiology","volume":"156 12","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11461142/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142382486","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

Structure and selectivity of a glutamate-specific TAXI TRAP binding protein from Vibrio cholerae. 霍乱弧菌中谷氨酸特异性 TAXI TRAP 结合蛋白的结构和选择性。

IF 3.3 2区医学

Journal of General Physiology Pub Date : 2024-12-02 Epub Date: 2024-11-18 DOI: 10.1085/jgp.202413584

Joseph F S Davies, Andrew Daab, Nicholas Massouh, Corey Kirkland, Bernadette Strongitharm, Andrew Leech, Marta Farré, Gavin H Thomas, Christopher Mulligan

{"title":"Structure and selectivity of a glutamate-specific TAXI TRAP binding protein from Vibrio cholerae.","authors":"Joseph F S Davies, Andrew Daab, Nicholas Massouh, Corey Kirkland, Bernadette Strongitharm, Andrew Leech, Marta Farré, Gavin H Thomas, Christopher Mulligan","doi":"10.1085/jgp.202413584","DOIUrl":"10.1085/jgp.202413584","url":null,"abstract":"Tripartite ATP-independent periplasmic (TRAP) transporters are widespread in prokaryotes and are responsible for the transport of a variety of different ligands, primarily organic acids. TRAP transporters can be divided into two subclasses; DctP-type and TAXI type, which share the same overall architecture and substrate-binding protein requirement. DctP-type transporters are very well studied and have been shown to transport a range of compounds including dicarboxylates, keto acids, and sugar acids. However, TAXI-type transporters are relatively poorly understood. To address this gap in our understanding, we have structurally and biochemically characterized VC0430 from Vibrio cholerae. We show it is a monomeric, high affinity glutamate-binding protein, which we thus rename VcGluP. VcGluP is stereoselective, binding the L-isomer preferentially, and can also bind L-glutamine and L-pyroglutamate with lower affinity. Structural characterization of ligand-bound VcGluP revealed details of its binding site and biophysical characterization of binding site mutants revealed the substrate binding determinants, which differ substantially from those of DctP-type TRAPs. Finally, we have analyzed the interaction between VcGluP and its cognate membrane component, VcGluQM (formerly VC0429) in silico, revealing an architecture hitherto unseen. To our knowledge, this is the first transporter in V. cholerae to be identified as specific to glutamate, which plays a key role in the osmoadaptation of V. cholerae, making this transporter a potential therapeutic target.","PeriodicalId":54828,"journal":{"name":"Journal of General Physiology","volume":"156 12","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142669661","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Myosin-binding protein-H: Not just filler. 肌球蛋白结合蛋白-H：不仅仅是填充物。

IF 3.3 2区医学

Journal of General Physiology Pub Date : 2024-12-02 Epub Date: 2024-11-01 DOI: 10.1085/jgp.202413622

David Y Barefield

引用次数: 0

Correction: Functional role of myosin-binding protein H in thick filaments of developing vertebrate fast-twitch skeletal muscle. 更正：肌球蛋白结合蛋白 H 在发育中脊椎动物快节奏骨骼肌粗丝中的功能作用。

IF 3.3 2区医学

Journal of General Physiology Pub Date : 2024-12-02 Epub Date: 2024-11-13 DOI: 10.1085/jgp.20241360411072024c

Andrew F Mead, Neil B Wood, Shane R Nelson, Bradley M Palmer, Lin Yang, Samantha Beck Previs, Angela Ploysangngam, Guy G Kennedy, Jennifer F McAdow, Sarah M Tremble, Marcus A Zimmermann, Marilyn J Cipolla, Alicia M Ebert, Aaron N Johnson, Christina A Gurnett, Michael J Previs, David M Warshaw

引用次数: 0

Piezo2 interacts with E-cadherin in specialized gastrointestinal epithelial mechanoreceptors. 在特化的胃肠道上皮机械感受器中，Piezo2 与 E-cadherin 相互作用。

IF 3.3 2区医学

Journal of General Physiology Pub Date : 2024-12-02 Epub Date: 2024-11-04 DOI: 10.1085/jgp.202213324

Arnaldo Mercado-Perez, Jeric P Hernandez, Yaroslav Fedyshyn, Anthony J Treichel, Vikram Joshi, Kimberlee Kossick, Kalpana R Betageri, Gianrico Farrugia, Brooke Druliner, Arthur Beyder

{"title":"Piezo2 interacts with E-cadherin in specialized gastrointestinal epithelial mechanoreceptors.","authors":"Arnaldo Mercado-Perez, Jeric P Hernandez, Yaroslav Fedyshyn, Anthony J Treichel, Vikram Joshi, Kimberlee Kossick, Kalpana R Betageri, Gianrico Farrugia, Brooke Druliner, Arthur Beyder","doi":"10.1085/jgp.202213324","DOIUrl":"10.1085/jgp.202213324","url":null,"abstract":"Piezo2 is a mechanically gated ion channel most commonly expressed by specialized mechanoreceptors, such as the enteroendocrine cells (EECs) of the gastrointestinal epithelium. A subpopulation of EECs expresses Piezo2 and functionally resembles the skin's touch sensors, called Merkel cells. Low-magnitude mechanical stimuli delivered to the mucosal layer are primarily sensed by mechanosensitive EECs in a process we term \"gut touch.\" Piezo2 transduces cellular forces into ionic currents, a process that is sensitive to bilayer tension and cytoskeletal depolymerization. E-cadherin is a widely expressed protein that mediates cell-cell adhesion in epithelia and interacts with scaffold proteins that anchor it to actin fibers. E-cadherin was shown to interact with Piezo2 in immortalized cell models. We hypothesized that the Piezo2-E-cadherin interaction is important for EEC mechanosensitivity. To test this, we used super-resolution imaging, co-immunoprecipitation, and functional assays in primary tissues from mice and gut organoids. In tissue EECs and intestinal organoids, we observed multiple Piezo2 cellular pools, including one that overlaps with actin and E-cadherin at the cells' lateral walls. Further, E-cadherin co-immunoprecipitated with Piezo2 in the primary colonic epithelium. We found that E-cadherin knockdown decreases mechanosensitive calcium responses in mechanically stimulated primary EECs. In all, our results demonstrate that Piezo2 localizes to the lateral wall of EECs, where it physically interacts with E-cadherin and actin. They suggest that the Piezo2-E-cadherin-actin interaction is important for mechanosensitivity in the gut epithelium and possibly in tissues where E-cadherin and Piezo2 are co-expressed in epithelial mechanoreceptors, such as skin, lung, and bladder.","PeriodicalId":54828,"journal":{"name":"Journal of General Physiology","volume":"156 12","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11536063/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142570381","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

Stable oxidative posttranslational modifications alter the gating properties of RyR1. 稳定的氧化翻译后修饰改变了 RyR1 的门控特性。

IF 3.3 2区医学

Journal of General Physiology Pub Date : 2024-12-02 Epub Date: 2024-11-05 DOI: 10.1085/jgp.202313515

Maarten M Steinz, Nicole Beard, Emily Shorter, Johanna T Lanner

{"title":"Stable oxidative posttranslational modifications alter the gating properties of RyR1.","authors":"Maarten M Steinz, Nicole Beard, Emily Shorter, Johanna T Lanner","doi":"10.1085/jgp.202313515","DOIUrl":"10.1085/jgp.202313515","url":null,"abstract":"The ryanodine receptor type 1 (RyR1) is a Ca2+ release channel that regulates skeletal muscle contraction by controlling Ca2+ release from the sarcoplasmic reticulum (SR). Posttranslational modifications (PTMs) of RyR1, such as phosphorylation, S-nitrosylation, and carbonylation are known to increase RyR1 open probability (Po), contributing to SR Ca2+ leak and skeletal muscle dysfunction. PTMs on RyR1 have been linked to muscle dysfunction in diseases like breast cancer, rheumatoid arthritis, Duchenne muscle dystrophy, and aging. While reactive oxygen species (ROS) and oxidative stress induce PTMs, the impact of stable oxidative modifications like 3-nitrotyrosine (3-NT) and malondialdehyde adducts (MDA) on RyR1 gating remains unclear. Mass spectrometry and single-channel recordings were used to study how 3-NT and MDA modify RyR1 and affect Po. Both modifications increased Po in a dose-dependent manner, with mass spectrometry identifying 30 modified residues out of 5035 amino acids per RyR1 monomer. Key modifications were found in domains critical for protein interaction and channel activation, including Y808/3NT in SPRY1, Y1081/3NT and H1254/MDA in SPRY2&3, and Q2107/MDA and Y2128/3NT in JSol, near the binding site of FKBP12. Though these modifications did not directly overlap with FKBP12 binding residues, they promoted FKBP12 dissociation from RyR1. These findings provide detailed insights into how stable oxidative PTMs on RyR1 residues alter channel gating, advancing our understanding of RyR1-mediated Ca2+ release in conditions associated with oxidative stress and muscle weakness.","PeriodicalId":54828,"journal":{"name":"Journal of General Physiology","volume":"156 12","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11540854/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142583565","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 new stress test for ryanodine receptors. 新的雷诺丁受体压力测试

IF 3.3 2区医学

Journal of General Physiology Pub Date : 2024-12-02 Epub Date: 2024-11-19 DOI: 10.1085/jgp.202413716

Ben Short

引用次数: 0

Mechanism of acid-sensing ion channel modulation by Hi1a. Hi1a 对酸感应离子通道的调节机制

IF 3.3 2区医学

Journal of General Physiology Pub Date : 2024-12-02 Epub Date: 2024-10-24 DOI: 10.1085/jgp.202313519

Kyle D Berger, David M MacLean

{"title":"Mechanism of acid-sensing ion channel modulation by Hi1a.","authors":"Kyle D Berger, David M MacLean","doi":"10.1085/jgp.202313519","DOIUrl":"10.1085/jgp.202313519","url":null,"abstract":"Acid-sensing ion channels (ASICs) are trimeric cation-selective channels activated by extracellular acidification. Amongst many pathological roles, ASICs are an important mediator of ischemic cell death and hence an attractive drug target for stroke treatment as well as other conditions. A peptide called Hi1a, isolated from Australian funnel web spider venom, inhibits ASIC1a and attenuates cell death in a stroke model up to 8 h after stroke induction. Here, we set out to understand the molecular basis for Hi1a's action. Hi1a is a bivalent toxin with two inhibitory cystine knot domains joined by a short linker. We found that both Hi1a domains modulate human ASIC1a gating with the N-terminal domain impairing channel activation while the C-terminal domain produces a \"pro-open\" phenotype even at submicromolar concentrations. Interestingly, both domains bind at the same site since a single point mutation, F352A, abolishes functional effects and reduces toxin affinity in surface plasmon resonance measurements. Therefore, the action of Hi1a at ASIC1a appears to arise through a mutually exclusive binding model where either the N or C domain of a single Hi1a binds one ASIC1a subunit. An ASIC1a trimer may bind several inhibitory N domains and one or more pro-open C domains at any one time, accounting for the incomplete inhibition of wild type Hi1a. We also found that the functional differences between these two domains are partially transferred by mutagenesis, affording new insight into the channel function and possible novel avenues of drug design.","PeriodicalId":54828,"journal":{"name":"Journal of General Physiology","volume":"156 12","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11513431/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142513210","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