Journal of General Physiology最新文献_第2页

A complete set of rate constants for a transporter's catalytic cycle. 转运体催化循环的一整套速率常数。

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.202513766

Michael L Jennings

引用次数: 0

How the Blind Watchmaker messed around with potassium channels. 盲人钟表匠是如何搞乱钾通道的。

IF 3.3 2区医学

Journal of General Physiology Pub Date : 2025-05-05 Epub Date: 2025-03-19 DOI: 10.1085/jgp.202513783

Lawrence Salkoff

引用次数: 0

Ctenophores and parahoxozoans independently evolved functionally diverse voltage-gated K+ channels. 栉水母和副嗜虫各自独立进化出功能多样的电压门控K+通道。

IF 3.3 2区医学

Journal of General Physiology Pub Date : 2025-05-05 Epub Date: 2025-03-18 DOI: 10.1085/jgp.202413740

Benjamin T Simonson, Zhaoyang Jiang, Joseph F Ryan, Timothy Jegla

{"title":"Ctenophores and parahoxozoans independently evolved functionally diverse voltage-gated K+ channels.","authors":"Benjamin T Simonson, Zhaoyang Jiang, Joseph F Ryan, Timothy Jegla","doi":"10.1085/jgp.202413740","DOIUrl":"10.1085/jgp.202413740","url":null,"abstract":"The ctenophore species Mnemiopsis leidyi is known to have a large set of voltage-gated K+ channels, but little is known about the functional diversity of these channels or their evolutionary history in other ctenophore species. Here, we searched the genomes of two additional ctenophore species, Beroe ovata and Hormiphora californensis, for voltage-gated K+ channels and functionally expressed a subset of M. leidyi channels. We found that the last common ancestor of these three disparate ctenophore lineages probably had at least 33 voltage-gated K+ channels. Two of these genes belong to the EAG family, and the remaining 31 belong to the Shaker family and form a single clade within the animal/choanoflagellate Shaker phylogeny. We additionally found evidence for 10 of these Shaker channels in a transcriptome of the early branching ctenophore lineage Euplokamis dunlapae, suggesting that the diversification of these channels was already underway early in ctenophore evolution. We functionally expressed 16 Mnemiopsis Shakers and found that they encode a diverse array of voltage-gated K+ conductances with functional orthologs for many classic Shaker family subtypes found in cnidarians and bilaterians. Analysis of Mnemiopsis transcriptome data show these 16 Shaker channels are expressed in a wide variety of cell types, including neurons, muscle, comb cells, and colloblasts. Ctenophores therefore appear to have independently evolved much of the voltage-gated K+ channel diversity that is shared between cnidarians and bilaterians.","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/PMC11917167/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143658984","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

Projections from ventral hippocampus to nucleus accumbens' cholinergic neurons are altered in depression. 抑郁症患者海马腹侧向伏隔核胆碱能神经元的投射发生改变。

IF 3.3 2区医学

Journal of General Physiology Pub Date : 2025-05-05 Epub Date: 2025-03-07 DOI: 10.1085/jgp.202413693

Lucian Medrihan, Margarete G Knudsen, Tatiana Ferraro, Pedro Del Cioppo Vasques, Yevgeniy Romin, Sho Fujisawa, Paul Greengard, Ana Milosevic

{"title":"Projections from ventral hippocampus to nucleus accumbens' cholinergic neurons are altered in depression.","authors":"Lucian Medrihan, Margarete G Knudsen, Tatiana Ferraro, Pedro Del Cioppo Vasques, Yevgeniy Romin, Sho Fujisawa, Paul Greengard, Ana Milosevic","doi":"10.1085/jgp.202413693","DOIUrl":"10.1085/jgp.202413693","url":null,"abstract":"The cholinergic interneurons (ChIs) of the nucleus accumbens (NAc) have a critical role in the activity of this region, specifically in the context of major depressive disorder. To understand the circuitry regulating this behavior, we sought to determine the areas that directly project to these interneurons by utilizing the monosynaptic cell-specific tracing technique. Mapping showed monosynaptic projections that are exclusive to NAc ChIs. To determine if some of these projections are altered in a depression mouse model, we used mice that do not express the calcium-binding protein p11 specifically in ChIs (ChAT-p11 cKO) and display a depressive-like phenotype. Our data demonstrated that while the overall projection areas remain similar between wild type and ChAT-p11 cKO mice, the number of projections from the ventral hippocampus (vHIP) is significantly reduced in the ChAT-p11 cKO mice. Furthermore, using optogenetics and electrophysiology we showed that glutamatergic projections from vHIP to NAc ChIs are severely altered in mutant mice. These results show that specific alterations in the circuitry of the accumbal ChIs could play an important role in the regulation of depressive-like behavior, reward-seeking behavior in addictions, or psychiatric symptoms in neurodegenerative diseases.","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/PMC11893161/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143574619","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

Examination of conformational dynamics of AdiC transporter with fluorescence-polarization microscopy. 用荧光偏振显微镜检查AdiC转运体的构象动力学。

IF 3.3 2区医学

Journal of General Physiology Pub Date : 2025-05-05 Epub Date: 2025-02-20 DOI: 10.1085/jgp.202413709

John H Lewis, Yufeng Zhou, Zhe Lu

{"title":"Examination of conformational dynamics of AdiC transporter with fluorescence-polarization microscopy.","authors":"John H Lewis, Yufeng Zhou, Zhe Lu","doi":"10.1085/jgp.202413709","DOIUrl":"10.1085/jgp.202413709","url":null,"abstract":"To understand the mechanism underlying the ability of individual AdiC molecules to transport arginine and agmatine, we used a recently developed high-resolution single-molecule fluorescence-polarization microscopy method to investigate conformation-specific changes in the emission polarization of a bifunctional fluorophore attached to an AdiC molecule. With this capability, we resolved AdiC's four conformations characterized by distinct spatial orientations in the absence or presence of the two substrates, and furthermore, each conformation's two energetic states, totaling 24 states. From the lifetimes of individual states and state-to-state transition probabilities, we determined 60 rate constants characterizing the transitions and 4 KD values characterizing the interactions of AdiC's two sides with arginine and agmatine, quantitatively defining a 24-state model. This model satisfactorily predicts the observed Michaelis-Menten behaviors of AdiC. With the acquired temporal information and existing structural information, we illustrated how to build an experiment-based integrative 4D model to capture and exhibit the complex spatiotemporal mechanisms underlying facilitated transport of substrates. However, inconsistent with what is expected from the prevailing hypothesis that AdiC is a 1:1 exchanger, all observed conformations transitioned among themselves with or without the presence of substrates. To corroborate this unexpected finding, we performed radioactive flux assays and found that the results are also incompatible with the hypothesis. As a technical advance, we showed that a monofunctional and the standard bifunctional fluorophore labels report comparable spatial orientation information defined in a local frame of reference. Here, the successful determination of the complex conformation-kinetic mechanism of AdiC demonstrates the unprecedented resolving power of the present microscopy method.","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/PMC11841622/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143460854","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 realistic look at rod synapses. 杆状突触的现实观察。

IF 3.3 2区医学

Journal of General Physiology Pub Date : 2025-05-05 Epub Date: 2025-04-16 DOI: 10.1085/jgp.202513804

Ben Short

引用次数: 0

In silico characterization of the gating and selectivity mechanism of the human TPC2 cation channel. 人TPC2阳离子通道的门控和选择性机制的硅表征。

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. 肌球蛋白结合蛋白c调节啮齿动物渗透心肌细胞负荷肌节缩短。

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

The architecture of invaginating rod synapses slows glutamate diffusion and shapes synaptic responses. 内翻杆突触的结构减缓谷氨酸扩散并形成突触反应。

IF 3.3 2区医学

Journal of General Physiology Pub Date : 2025-05-05 Epub Date: 2025-02-28 DOI: 10.1085/jgp.202413746

Wallace B Thoreson, Thomas M Bartol, Nicholas H Conoan, Jeffrey S Diamond

{"title":"The architecture of invaginating rod synapses slows glutamate diffusion and shapes synaptic responses.","authors":"Wallace B Thoreson, Thomas M Bartol, Nicholas H Conoan, Jeffrey S Diamond","doi":"10.1085/jgp.202413746","DOIUrl":"10.1085/jgp.202413746","url":null,"abstract":"Synapses of retinal rod photoreceptors involve deep invaginations occupied by second-order rod bipolar cell (RBP) and horizontal cell (HC) dendrites. Synaptic vesicles are released into this invagination at multiple sites beneath an elongated presynaptic ribbon. To study the impact of this architecture on glutamate diffusion and receptor activity, we reconstructed four rod terminals and their postsynaptic dendrites from serial electron micrographs of the mouse retina. We incorporated these structures into anatomically realistic Monte Carlo simulations of neurotransmitter diffusion and receptor activation. By comparing passive diffusion of glutamate in realistic structures with geometrically simplified models, we found that glutamate exits anatomically realistic synapses 10-fold more slowly than previously predicted. Constraining simulations with physiological data, we modeled activity of EAAT5 glutamate transporters in rods, AMPA receptors on HC dendrites, and metabotropic glutamate receptors (mGluR6) on RBP dendrites. Simulations suggested that ∼3,000 EAAT5 populate rod membranes. While uptake by surrounding glial Müller cells retrieves most glutamate released by rods, binding and uptake by EAAT5 influence RBP kinetics. Glutamate persistence allows mGluR6 on RBP dendrites to integrate the stream of vesicles released by rods in darkness. Glutamate's tortuous diffusional path confers quantal variability, as release from nearby ribbon sites exerts larger effects on RBP and HC receptors than release from more distant sites. Temporal integration supports slower sustained release rates, but additional quantal variability can impede postsynaptic detection of changes in release produced by rod light responses. These results show an example of the profound impact that synaptic architecture can have on postsynaptic responses.","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/PMC11869902/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143525136","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. 了解电压门控钠离子通道突变在心血管疾病中的作用。

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