Journal of General Physiology最新文献_第10页

Tail length and E525K dilated cardiomyopathy mutant alter human β-cardiac myosin super-relaxed state. 尾巴长度和 E525K 扩张型心肌病突变体改变了人类 β-心肌酶的超松弛状态。

IF 3.3 2区医学

Journal of General Physiology Pub Date : 2024-06-03 Epub Date: 2024-05-06 DOI: 10.1085/jgp.202313522

Sebastian Duno-Miranda, Shane R Nelson, David V Rasicci, Skylar M L Bodt, Joseph A Cirilo, Duha Vang, Sivaraj Sivaramakrishnan, Christopher M Yengo, David M Warshaw

{"title":"Tail length and E525K dilated cardiomyopathy mutant alter human β-cardiac myosin super-relaxed state.","authors":"Sebastian Duno-Miranda, Shane R Nelson, David V Rasicci, Skylar M L Bodt, Joseph A Cirilo, Duha Vang, Sivaraj Sivaramakrishnan, Christopher M Yengo, David M Warshaw","doi":"10.1085/jgp.202313522","DOIUrl":"10.1085/jgp.202313522","url":null,"abstract":"Dilated cardiomyopathy (DCM) is a condition characterized by impaired cardiac function, due to myocardial hypo-contractility, and is associated with point mutations in β-cardiac myosin, the molecular motor that powers cardiac contraction. Myocardial function can be modulated through sequestration of myosin motors into an auto-inhibited \"super-relaxed\" state (SRX), which may be further stabilized by a structural state known as the \"interacting heads motif\" (IHM). Here, we sought to determine whether hypo-contractility of DCM myocardium results from reduced function of individual myosin molecules or from decreased myosin availability to interact with actin due to increased IHM/SRX stabilization. We used an established DCM myosin mutation, E525K, and characterized the biochemical and mechanical activity of wild-type and mutant human β-cardiac myosin constructs that differed in the length of their coiled-coil tail, which dictates their ability to form the IHM/SRX state. We found that short-tailed myosin constructs exhibited low IHM/SRX content, elevated actin-activated ATPase activity, and fast velocities in unloaded motility assays. Conversely, longer-tailed constructs exhibited higher IHM/SRX content and reduced actomyosin ATPase and velocity. Our modeling suggests that reduced velocities may be attributed to IHM/SRX-dependent sequestration of myosin heads. Interestingly, longer-tailed E525K mutants showed no apparent impact on velocity or actomyosin ATPase at low ionic strength but stabilized IHM/SRX state at higher ionic strength. Therefore, the hypo-contractility observed in DCM may be attributable to reduced myosin head availability caused by enhanced IHM/SRX stability in E525K mutants.","PeriodicalId":54828,"journal":{"name":"Journal of General Physiology","volume":"156 6","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11074782/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140866250","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's powerstroke transitions define atomic scale movement of cardiac thin filament tropomyosin. 肌球蛋白的动力冲程转换确定了心脏细丝肌球蛋白的原子尺度运动。

IF 3.3 2区医学

Journal of General Physiology Pub Date : 2024-05-06 Epub Date: 2024-04-12 DOI: 10.1085/jgp.202413538

Michael J Rynkiewicz, Matthew C Childers, Olga E Karpicheva, Michael Regnier, Michael A Geeves, William Lehman

{"title":"Myosin's powerstroke transitions define atomic scale movement of cardiac thin filament tropomyosin.","authors":"Michael J Rynkiewicz, Matthew C Childers, Olga E Karpicheva, Michael Regnier, Michael A Geeves, William Lehman","doi":"10.1085/jgp.202413538","DOIUrl":"10.1085/jgp.202413538","url":null,"abstract":"Dynamic interactions between the myosin motor head on thick filaments and the actin molecular track on thin filaments drive the myosin-crossbridge cycle that powers muscle contraction. The process is initiated by Ca2+ and the opening of troponin-tropomyosin-blocked myosin-binding sites on actin. The ensuing recruitment of myosin heads and their transformation from pre-powerstroke to post-powerstroke conformation on actin produce the force required for contraction. Cryo-EM-based atomic models confirm that during this process, tropomyosin occupies three different average positions on actin. Tropomyosin pivoting on actin away from a TnI-imposed myosin-blocking position accounts for part of the Ca2+ activation observed. However, the structure of tropomyosin on thin filaments that follows pre-powerstroke myosin binding and its translocation during myosin's pre-powerstroke to post-powerstroke transition remains unresolved. Here, we approach this transition computationally in silico. We used the myosin helix-loop-helix motif as an anchor to dock models of pre-powerstroke cardiac myosin to the cleft between neighboring actin subunits along cardiac thin filaments. We then performed targeted molecular dynamics simulations of the transition between pre- and post-powerstroke conformations on actin in the presence of cardiac troponin-tropomyosin. These simulations show Arg 369 and Glu 370 on the tip of myosin Loop-4 encountering identically charged residues on tropomyosin. The charge repulsion between residues causes tropomyosin translocation across actin, thus accounting for the final regulatory step in the activation of the thin filament, and, in turn, facilitating myosin movement along the filament. We suggest that during muscle activity, myosin-induced tropomyosin movement is likely to result in unencumbered myosin head interactions on actin at low-energy cost.","PeriodicalId":54828,"journal":{"name":"Journal of General Physiology","volume":"156 5","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11010328/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140860332","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

Honeybee CaV4 has distinct permeation, inactivation, and pharmacology from homologous NaV channels. 蜜蜂 CaV4 的渗透、失活和药理作用与同源的 NaV 通道截然不同。

IF 3.3 2区医学

Journal of General Physiology Pub Date : 2024-05-06 Epub Date: 2024-04-01 DOI: 10.1085/jgp.202313509

Anaïs Bertaud, Thierry Cens, Alain Chavanieu, Sébastien Estaran, Matthieu Rousset, Lisa Soussi, Claudine Ménard, Akelsso Kadala, Claude Collet, Sébastien Dutertre, Patrick Bois, Pascal Gosselin-Badaroudine, Jean-Baptiste Thibaud, Julien Roussel, Michel Vignes, Mohamed Chahine, Pierre Charnet

{"title":"Honeybee CaV4 has distinct permeation, inactivation, and pharmacology from homologous NaV channels.","authors":"Anaïs Bertaud, Thierry Cens, Alain Chavanieu, Sébastien Estaran, Matthieu Rousset, Lisa Soussi, Claudine Ménard, Akelsso Kadala, Claude Collet, Sébastien Dutertre, Patrick Bois, Pascal Gosselin-Badaroudine, Jean-Baptiste Thibaud, Julien Roussel, Michel Vignes, Mohamed Chahine, Pierre Charnet","doi":"10.1085/jgp.202313509","DOIUrl":"10.1085/jgp.202313509","url":null,"abstract":"DSC1, a Drosophila channel with sequence similarity to the voltage-gated sodium channel (NaV), was identified over 20 years ago. This channel was suspected to function as a non-specific cation channel with the ability to facilitate the permeation of calcium ions (Ca2+). A honeybee channel homologous to DSC1 was recently cloned and shown to exhibit strict selectivity for Ca2+, while excluding sodium ions (Na+), thus defining a new family of Ca2+ channels, known as CaV4. In this study, we characterize CaV4, showing that it exhibits an unprecedented type of inactivation, which depends on both an IFM motif and on the permeating divalent cation, like NaV and CaV1 channels, respectively. CaV4 displays a specific pharmacology with an unusual response to the alkaloid veratrine. It also possesses an inactivation mechanism that uses the same structural domains as NaV but permeates Ca2+ ions instead. This distinctive feature may provide valuable insights into how voltage- and calcium-dependent modulation of voltage-gated Ca2+ and Na+ channels occur under conditions involving local changes in intracellular calcium concentrations. Our study underscores the unique profile of CaV4 and defines this channel as a novel class of voltage-gated Ca2+ channels.","PeriodicalId":54828,"journal":{"name":"Journal of General Physiology","volume":"156 5","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10983803/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140337719","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: Optimization of CFTR gating through the evolution of its extracellular loops 更正：通过细胞外环的演化优化 CFTR 门控

IF 3.8 2区医学

Journal of General Physiology Pub Date : 2024-04-04 DOI: 10.1085/jgp.20221326403272024c

Márton A. Simon, László Csanády

引用次数: 0

Tirasemtiv enhances submaximal muscle tension in an Acta1:p.Asp286Gly mouse model of nemaline myopathy. Tirasemtiv能增强Acta1:p.Asp286Gly神经性肌病小鼠模型的亚极限肌肉张力。

IF 3.3 2区医学

Journal of General Physiology Pub Date : 2024-04-01 Epub Date: 2024-02-20 DOI: 10.1085/jgp.202313471

Ricardo A Galli, Tamara C Borsboom, Charlotte Gineste, Lorenza Brocca, Maira Rossi, Darren T Hwee, Fady I Malik, Roberto Bottinelli, Julien Gondin, Maria-Antonietta Pellegrino, Josine M de Winter, Coen A C Ottenheijm

{"title":"Tirasemtiv enhances submaximal muscle tension in an Acta1:p.Asp286Gly mouse model of nemaline myopathy.","authors":"Ricardo A Galli, Tamara C Borsboom, Charlotte Gineste, Lorenza Brocca, Maira Rossi, Darren T Hwee, Fady I Malik, Roberto Bottinelli, Julien Gondin, Maria-Antonietta Pellegrino, Josine M de Winter, Coen A C Ottenheijm","doi":"10.1085/jgp.202313471","DOIUrl":"10.1085/jgp.202313471","url":null,"abstract":"Nemaline myopathies are the most common form of congenital myopathies. Variants in ACTA1 (NEM3) comprise 15-25% of all nemaline myopathy cases. Patients harboring variants in ACTA1 present with a heterogeneous disease course characterized by stable or progressive muscle weakness and, in severe cases, respiratory failure and death. To date, no specific treatments are available. Since NEM3 is an actin-based thin filament disease, we tested the ability of tirasemtiv, a fast skeletal muscle troponin activator, to improve skeletal muscle function in a mouse model of NEM3, harboring the patient-based p.Asp286Gly variant in Acta1. Acute and long-term tirasemtiv treatment significantly increased muscle contractile capacity at submaximal stimulation frequencies in both fast-twitch extensor digitorum longus and gastrocnemius muscle, and intermediate-twitch diaphragm muscle in vitro and in vivo. Additionally, long-term tirasemtiv treatment in NEM3 mice resulted in a decreased respiratory rate with preserved minute volume, suggesting more efficient respiration. Altogether, our data support the therapeutic potential of fast skeletal muscle troponin activators in alleviating skeletal muscle weakness in a mouse model of NEM3 caused by the Acta1:p.Asp286Gly variant.","PeriodicalId":54828,"journal":{"name":"Journal of General Physiology","volume":"156 4","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10876480/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139906898","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

RyR2 phosphorylation alters dyad architecture. RyR2磷酸化改变了二联体结构。

IF 3.3 2区医学

Journal of General Physiology Pub Date : 2024-04-01 Epub Date: 2024-03-07 DOI: 10.1085/jgp.202413569

Ben Short

引用次数: 0

A novel, patient-derived RyR1 mutation impairs muscle function and calcium homeostasis in mice. 一种源自患者的新型 RyR1 突变会损害小鼠的肌肉功能和钙稳态。

IF 3.3 2区医学

Journal of General Physiology Pub Date : 2024-04-01 Epub Date: 2024-03-04 DOI: 10.1085/jgp.202313486

Sofia Benucci, Alexis Ruiz, Martina Franchini, Lucia Ruggiero, Dario Zoppi, Rebecca Sitsapesan, Chris Lindsay, Pawel Pelczar, Laura Pietrangelo, Feliciano Protasi, Susan Treves, Francesco Zorzato

{"title":"A novel, patient-derived RyR1 mutation impairs muscle function and calcium homeostasis in mice.","authors":"Sofia Benucci, Alexis Ruiz, Martina Franchini, Lucia Ruggiero, Dario Zoppi, Rebecca Sitsapesan, Chris Lindsay, Pawel Pelczar, Laura Pietrangelo, Feliciano Protasi, Susan Treves, Francesco Zorzato","doi":"10.1085/jgp.202313486","DOIUrl":"10.1085/jgp.202313486","url":null,"abstract":"RYR1 is the most commonly mutated gene associated with congenital myopathies, a group of early-onset neuromuscular conditions of variable severity. The functional effects of a number of dominant RYR1 mutations have been established; however, for recessive mutations, these effects may depend on multiple factors, such as the formation of a hypomorphic allele, or on whether they are homozygous or compound heterozygous. Here, we functionally characterize a new transgenic mouse model knocked-in for mutations identified in a severely affected child born preterm and presenting limited limb movement. The child carried the homozygous c.14928C>G RYR1 mutation, resulting in the p.F4976L substitution. In vivo and ex vivo assays revealed that homozygous mice fatigued sooner and their muscles generated significantly less force compared with their WT or heterozygous littermates. Electron microscopy, biochemical, and physiological analyses showed that muscles from RyR1 p.F4976L homozygous mice have the following properties: (1) contain fewer calcium release units and show areas of myofibrillar degeneration, (2) contain less RyR1 protein, (3) fibers show smaller electrically evoked calcium transients, and (4) their SR has smaller calcium stores. In addition, single-channel recordings indicate that RyR1 p.F4976L exhibits higher Po in the presence of 100 μM [Ca2+]. Our mouse model partly recapitulates the clinical picture of the homozygous human patient and provides significant insight into the functional impact of this mutation. These results will help understand the pathology of patients with similar RYR1 mutations.","PeriodicalId":54828,"journal":{"name":"Journal of General Physiology","volume":"156 4","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10911087/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140040934","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

Phosphorylation of RyR2 simultaneously expands the dyad and rearranges the tetramers. RyR2 的磷酸化同时扩大了二联体并重新排列了四聚体。

IF 3.3 2区医学

Journal of General Physiology Pub Date : 2024-04-01 Epub Date: 2024-02-22 DOI: 10.1085/jgp.202213108

Parisa Asghari, David R L Scriven, Saba Shahrasebi, Hector H Valdivia, Katherina M Alsina, Carmen R Valdivia, J Alberto Navarro-Garcia, Xander H T Wehrens, Edwin D W Moore

{"title":"Phosphorylation of RyR2 simultaneously expands the dyad and rearranges the tetramers.","authors":"Parisa Asghari, David R L Scriven, Saba Shahrasebi, Hector H Valdivia, Katherina M Alsina, Carmen R Valdivia, J Alberto Navarro-Garcia, Xander H T Wehrens, Edwin D W Moore","doi":"10.1085/jgp.202213108","DOIUrl":"10.1085/jgp.202213108","url":null,"abstract":"We have previously demonstrated that type II ryanodine receptors (RyR2) tetramers can be rapidly rearranged in response to a phosphorylation cocktail. The cocktail modified downstream targets indiscriminately, making it impossible to determine whether phosphorylation of RyR2 was an essential element of the response. Here, we used the β-agonist isoproterenol and mice homozygous for one of the following clinically relevant mutations: S2030A, S2808A, S2814A, or S2814D. We measured the length of the dyad using transmission electron microscopy (TEM) and directly visualized RyR2 distribution using dual-tilt electron tomography. We found that the S2814D mutation, by itself, significantly expanded the dyad and reorganized the tetramers, suggesting a direct link between the phosphorylation state of the tetramer and its microarchitecture. S2808A and S2814A mutant mice, as well as wild types, had significant expansions of their dyads in response to isoproterenol, while S2030A mutants did not. In agreement with functional data from these mutants, S2030 and S2808 were necessary for a complete β-adrenergic response, unlike S2814 mutants. Additionally, all mutants had unique effects on the organization of their tetramer arrays. Lastly, the correlation of structural with functional changes suggests that tetramer-tetramer contacts play an important functional role. We thus conclude that both the size of the dyad and the arrangement of the tetramers are linked to the state of the channel tetramer and can be dynamically altered by a β-adrenergic receptor agonist.","PeriodicalId":54828,"journal":{"name":"Journal of General Physiology","volume":"156 4","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10883851/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139934365","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: A dual-clock-driven model of lymphatic muscle cell pacemaking to emulate knock-out of Ano1 or IP3R. 更正：双时钟驱动的淋巴肌细胞起搏模型，以模拟敲除 Ano1 或 IP3R。

IF 3.8 2区医学

Journal of General Physiology Pub Date : 2024-03-04 Epub Date: 2024-01-31 DOI: 10.1085/jgp.20231335501222024c

Edward J Hancock, Scott D Zawieja, Charlie Macaskill, Michael J Davis, Christopher D Bertram

引用次数: 0

SMR transporters meet the challenge of metformin metabolites. SMR 转运体迎接二甲双胍代谢物的挑战。

IF 3.3 2区医学

Journal of General Physiology Pub Date : 2024-03-04 Epub Date: 2024-02-07 DOI: 10.1085/jgp.202413549

Ben Short

引用次数: 0