Journal of General Physiology最新文献_第5页

The S1 helix is a VIP in VSP. S1 螺旋线是 VSP 的 VIP。

IF 3.3 2区医学

Journal of General Physiology Pub Date : 2024-07-01 Epub Date: 2024-06-11 DOI: 10.1085/jgp.202413612

Ben Short

引用次数: 0

Niclosamide potentiates TMEM16A and induces vasoconstriction. 尼可刹米能增强 TMEM16A 的作用并诱导血管收缩。

IF 3.8 2区医学

Journal of General Physiology Pub Date : 2024-07-01 Epub Date: 2024-05-30 DOI: 10.1085/jgp.202313460

Pengfei Liang, Yui Chun S Wan, Kuai Yu, H Criss Hartzell, Huanghe Yang

{"title":"Niclosamide potentiates TMEM16A and induces vasoconstriction.","authors":"Pengfei Liang, Yui Chun S Wan, Kuai Yu, H Criss Hartzell, Huanghe Yang","doi":"10.1085/jgp.202313460","DOIUrl":"10.1085/jgp.202313460","url":null,"abstract":"The TMEM16A calcium-activated chloride channel is a promising therapeutic target for various diseases. Niclosamide, an anthelmintic medication, has been considered a TMEM16A inhibitor for treating asthma and chronic obstructive pulmonary disease (COPD) but was recently found to possess broad-spectrum off-target effects. Here, we show that, under physiological Ca2+ (200-500 nM) and voltages, niclosamide acutely potentiates TMEM16A. Our computational and functional characterizations pinpoint a putative niclosamide binding site on the extracellular side of TMEM16A. Mutations in this site attenuate the potentiation. Moreover, niclosamide potentiates endogenous TMEM16A in vascular smooth muscle cells, triggers intracellular calcium increase, and constricts the murine mesenteric artery. Our findings advise caution when considering clinical applications of niclosamide as a TMEM16A inhibitor. The identification of the putative niclosamide binding site provides insights into the mechanism of TMEM16A pharmacological modulation and provides insights into developing specific TMEM16A modulators to treat human diseases.","PeriodicalId":54828,"journal":{"name":"Journal of General Physiology","volume":"156 7","pages":""},"PeriodicalIF":3.8,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11138202/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141176989","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 mutation that prevents myosin from overcoming its inhibitions. 肌球蛋白发生突变，无法克服其抑制作用。

IF 3.3 2区医学

Journal of General Physiology Pub Date : 2024-06-03 Epub Date: 2024-05-10 DOI: 10.1085/jgp.202413594

Ben Short

引用次数: 0

Sensory transduction in auditory hair cells-PIEZOs can't touch this. 听觉毛细胞的感觉传导--PIEZOs 无法触及。

IF 3.3 2区医学

Journal of General Physiology Pub Date : 2024-06-03 Epub Date: 2024-05-10 DOI: 10.1085/jgp.202413585

Jeffrey R Holt, Robert Fettiplace, Ulrich Müller

引用次数: 0

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

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

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

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