Journal of General Physiology最新文献_第2页

In silico characterization of the gating and selectivity mechanism of the human TPC2 cation channel.

IF 3.3 2区医学

Journal of General Physiology Pub Date : 2025-05-05 Epub Date: 2025-02-21 DOI: 10.1085/jgp.202313506

Alp Tegin Şahin, Ulrich Zachariae

{"title":"In silico characterization of the gating and selectivity mechanism of the human TPC2 cation channel.","authors":"Alp Tegin Şahin, Ulrich Zachariae","doi":"10.1085/jgp.202313506","DOIUrl":"10.1085/jgp.202313506","url":null,"abstract":"Two-pore channels (TPCs) are twofold symmetric endolysosomal cation channels forming important drug targets, especially for antiviral drugs. They are activated by calcium, ligand binding, and membrane voltage, and to date, they are the only ion channels shown to alter their ion selectivity depending on the type of bound ligand. However, despite their importance, ligand activation of TPCs and the molecular mechanisms underlying their ion selectivity are still poorly understood. Here, we set out to elucidate the mechanistic basis for the ion selectivity of human TPC2 (hTPC2) and the molecular mechanism of ligand-induced channel activation by the lipid PI(3,5)P2. We performed all-atom in silico electrophysiology simulations to study Na+ and Ca2+ permeation across full-length hTPC2 on the timescale of ion conduction and investigated the conformational changes induced by the presence or absence of bound PI(3,5)P2. Our findings reveal that hTPC2 adopts distinct conformations depending on the presence of PI(3,5)P2 and elucidate the allosteric transition pathways between these structures. Additionally, we examined the permeation mechanism, solvation states, and binding sites of ions during ion permeation through the pore. The results of our simulations explain the experimental observation that hTPC2 is more selective for Na+ over Ca2+ ions in the presence of PI(3,5)P2via a multilayer selectivity mechanism. Importantly, mutations in the selectivity filter region of hTPC2 maintain cation conduction but change the ion selectivity of hTPC2 drastically.","PeriodicalId":54828,"journal":{"name":"Journal of General Physiology","volume":"157 3","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11844439/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143469929","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

Myosin binding protein-C modulates loaded sarcomere shortening in rodent permeabilized cardiac myocytes.

IF 3.3 2区医学

Journal of General Physiology Pub Date : 2025-05-05 Epub Date: 2025-03-24 DOI: 10.1085/jgp.202413678

Kerry S McDonald, Theodore J Kalogeris, Adam B Veteto, Daniel J Davis, Laurin M Hanft

{"title":"Myosin binding protein-C modulates loaded sarcomere shortening in rodent permeabilized cardiac myocytes.","authors":"Kerry S McDonald, Theodore J Kalogeris, Adam B Veteto, Daniel J Davis, Laurin M Hanft","doi":"10.1085/jgp.202413678","DOIUrl":"10.1085/jgp.202413678","url":null,"abstract":"During the ejection phase of the cardiac cycle, left ventricular (LV) cardiac myocytes undergo loaded shortening and generate power. However, few studies have measured sarcomere shortening during loaded contractions. Here, we simultaneously monitored muscle length (ML) and sarcomere length (SL) during isotonic contractions in rodent permeabilized LV cardiac myocyte preparations. In permeabilized cardiac myocyte preparations from rats, we found that ML and SL traces were closely matched, as SL velocities were within ∼77% of ML velocities during half-maximal Ca2+ activations. We next tested whether cardiac myosin binding protein-C (cMyBP-C) regulates loaded shortening and power output by modulating cross-bridge availability. We characterized force-velocity and power-load relationships in wildtype (WT) and cMyBP-C deficient (Mybpc3-/-) mouse permeabilized cardiac myocyte preparations, at both the ML and SL level, before and after treatment with the small molecule myosin inhibitor, mavacamten. We found that SL traces closely matched ML traces in both WT and Mybpc3-/- cardiac myocytes. However, Mybpc3-/- cardiac myocytes exhibited disproportionately high sarcomere shortening velocities at high loads. Interestingly, in Mybpc3-/- cardiac myocytes, 0.5 µM mavacamten slowed SL-loaded shortening across the force-velocity curve and normalized SL shortening velocity at high loads. Overall, these results suggest that cMyBP-C moderates sarcomere-loaded shortening, especially at high loads, at least in part, by modulating cross-bridge availability.","PeriodicalId":54828,"journal":{"name":"Journal of General Physiology","volume":"157 3","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11932042/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143694693","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

Understanding the role of mutations in voltage-gated sodium ion channels for cardiovascular disorders.

IF 3.3 2区医学

Journal of General Physiology Pub Date : 2025-03-03 Epub Date: 2025-01-23 DOI: 10.1085/jgp.202413744

Christian Jorgensen

引用次数: 0

Modeling cardiac contractile cooperativity across species.

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.

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

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

Inactivation of CaV1 and CaV2 channels.

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

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

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