Journal of General Physiology最新文献_第4页

Regulation of NMDAR activation efficiency by environmental factors and subunit composition. 环境因素和亚基组成对 NMDAR 激活效率的调控

IF 3.3 2区医学

Journal of General Physiology Pub Date : 2025-01-06 Epub Date: 2024-11-22 DOI: 10.1085/jgp.202413637

Miaomiao He, Lonnie P Wollmuth

{"title":"Regulation of NMDAR activation efficiency by environmental factors and subunit composition.","authors":"Miaomiao He, Lonnie P Wollmuth","doi":"10.1085/jgp.202413637","DOIUrl":"10.1085/jgp.202413637","url":null,"abstract":"NMDA receptors (NMDAR) convert the major excitatory neurotransmitter glutamate into a synaptic signal. A key question is how efficiently the ion channel opens in response to the rapid exposure to presynaptic glutamate release. Here, we applied glutamate to single channel outside-out patches and measured the successes of channel openings and the latency to first opening to assay the activation efficiency of NMDARs under different physiological conditions and with different human subunit compositions. For GluN1/GluN2A receptors, we find that various factors, including intracellular ATP and GTP, can enhance the efficiency of activation presumably via the intracellular C-terminal domain. Notably, an energy-based internal solution or increasing the time between applications to increase recovery time improved efficiency. However, even under these optimized conditions and with a 1-s glutamate application, there remained around 10-15% inefficiency. Channel activation became more inefficient with brief synaptic-like pulses of glutamate at 2 ms. Of the different NMDAR subunit compositions, GluN2B-containing NMDARs showed the lowest success rate and longest latency to first openings, highlighting that they display the most distinct activation mechanism. In contrast, putative triheteromeric GluN1/GluN2A/GluN2B receptors showed high activation efficiency. Despite the low open probability, NMDARs containing either GluN2C or GluN2D subunits displayed high activation efficiency, nearly comparable with that for GluN2A-containing receptors. These results highlight that activation efficiency in NMDARs can be regulated by environmental surroundings and varies across different subunits.","PeriodicalId":54828,"journal":{"name":"Journal of General Physiology","volume":"157 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11586625/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142689793","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 calcium-binding protein S100A1 binds to titin's N2A insertion sequence in a pH-dependent manner. 钙结合蛋白S100A1以ph依赖的方式与titin的N2A插入序列结合。

IF 3.3 2区医学

Journal of General Physiology Pub Date : 2025-01-06 Epub Date: 2024-12-31 DOI: 10.1085/jgp.202313472

Sabrina I Apel, Emily Schaffter, Nicholas Melisi, Matthew J Gage

{"title":"The calcium-binding protein S100A1 binds to titin's N2A insertion sequence in a pH-dependent manner.","authors":"Sabrina I Apel, Emily Schaffter, Nicholas Melisi, Matthew J Gage","doi":"10.1085/jgp.202313472","DOIUrl":"10.1085/jgp.202313472","url":null,"abstract":"Titin is the third contractile filament in the sarcomere, and it plays a critical role in sarcomere integrity and both passive and active tension. Unlike the thick and thin filaments, which are polymers of myosin and actin, respectively, titin is a single protein that spans from Z-disk to M-line. The N2A region within titin has been identified as a signaling hub for the muscle and is shown to be involved in multiple interactions. The insertion sequence (UN2A) within the N2A region was predicted as a potential binding site for the Ca2+-binding protein, S100A1. We demonstrate using a combination of size exclusion chromatography, surface plasmon resonance, and fluorescence resonance energy transfer that S100A1 can bind to the UN2A region. We further demonstrate that this interaction occurs under conditions where calcium is bound to S100A1, suggesting that the conformational shift in S100A1 when calcium binds is important. We also observed a conformational change in UN2A induced by shifts in pH, suggesting that conformational flexibility in UN2A plays a critical role in the interaction with S100A1. These results lead us to propose that the interaction of S100A1 and UN2A might act as a sensor to regulate titin's function in response to physiological changes in the muscle.","PeriodicalId":54828,"journal":{"name":"Journal of General Physiology","volume":"157 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11687307/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142907705","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

Isoform-specific N-linked glycosylation of NaV channel α-subunits alters β-subunit binding sites. NaV通道α亚基的同工酶特异性N-连接糖基化改变了β亚基的结合位点。

IF 3.3 2区医学

Journal of General Physiology Pub Date : 2025-01-06 Epub Date: 2024-12-16 DOI: 10.1085/jgp.202413609

Christopher A Beaudoin, Manas Kohli, Samantha C Salvage, Hengrui Liu, Samuel J Arundel, Samir W Hamaia, Ming Lei, Christopher L-H Huang, Antony P Jackson

{"title":"Isoform-specific N-linked glycosylation of NaV channel α-subunits alters β-subunit binding sites.","authors":"Christopher A Beaudoin, Manas Kohli, Samantha C Salvage, Hengrui Liu, Samuel J Arundel, Samir W Hamaia, Ming Lei, Christopher L-H Huang, Antony P Jackson","doi":"10.1085/jgp.202413609","DOIUrl":"10.1085/jgp.202413609","url":null,"abstract":"Voltage-gated sodium channel α-subunits (NaV1.1-1.9) initiate and propagate action potentials in neurons and myocytes. The NaV β-subunits (β1-4) have been shown to modulate α-subunit properties. Homo-oligomerization of β-subunits on neighboring or opposing plasma membranes has been suggested to facilitate cis or trans interactions, respectively. The interactions between several NaV channel isoforms and β-subunits have been determined using cryogenic electron microscopy (cryo-EM). Interestingly, the NaV cryo-EM structures reveal the presence of N-linked glycosylation sites. However, only the first glycan moieties are typically resolved at each site due to the flexibility of mature glycan trees. Thus, existing cryo-EM structures may risk de-emphasizing the structural implications of glycans on the NaV channels. Herein, molecular modeling and all-atom molecular dynamics simulations were applied to investigate the conformational landscape of N-linked glycans on NaV channel surfaces. The simulations revealed that negatively charged sialic acid residues of two glycan sites may interact with voltage-sensing domains. Notably, two NaV1.5 isoform-specific glycans extensively cover the α-subunit region that, in other NaV channel α-subunit isoforms, corresponds to the binding site for the β1- (and likely β3-) subunit immunoglobulin (Ig) domain. NaV1.8 contains a unique N-linked glycosylation site that likely prevents its interaction with the β2 and β4-subunit Ig-domain. These isoform-specific glycans may have evolved to facilitate specific functional interactions, for example, by redirecting β-subunit Ig-domains outward to permit cis or trans supraclustering within specialized cellular compartments such as the cardiomyocyte perinexal space. Further experimental work is necessary to validate these predictions.","PeriodicalId":54828,"journal":{"name":"Journal of General Physiology","volume":"157 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11666101/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142830466","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

Mechanisms underlying dilated cardiomyopathy associated with FKBP12 deficiency. 扩张型心肌病与FKBP12缺乏相关的机制。

IF 3.3 2区医学

Journal of General Physiology Pub Date : 2025-01-06 Epub Date: 2024-12-11 DOI: 10.1085/jgp.202413583

Amy D Hanna, Ting Chang, Kevin S Ho, Rachel Sue Zhen Yee, William Cameron Walker, Nadia Agha, Chih-Wei Hsu, Sung Yun Jung, Mary E Dickinson, Md Abul Hassan Samee, Christopher S Ward, Chang Seok Lee, George G Rodney, Susan L Hamilton

{"title":"Mechanisms underlying dilated cardiomyopathy associated with FKBP12 deficiency.","authors":"Amy D Hanna, Ting Chang, Kevin S Ho, Rachel Sue Zhen Yee, William Cameron Walker, Nadia Agha, Chih-Wei Hsu, Sung Yun Jung, Mary E Dickinson, Md Abul Hassan Samee, Christopher S Ward, Chang Seok Lee, George G Rodney, Susan L Hamilton","doi":"10.1085/jgp.202413583","DOIUrl":"10.1085/jgp.202413583","url":null,"abstract":"Dilated cardiomyopathy (DCM) is a highly prevalent and genetically heterogeneous condition that results in decreased contractility and impaired cardiac function. The FK506-binding protein FKBP12 has been implicated in regulating the ryanodine receptor in skeletal muscle, but its role in cardiac muscle remains unclear. To define the effect of FKBP12 in cardiac function, we generated conditional mouse models of FKBP12 deficiency. We used Cre recombinase driven by either the α-myosin heavy chain, (αMHC) or muscle creatine kinase (MCK) promoter, which are expressed at embryonic day 9 (E9) and E13, respectively. Both conditional models showed an almost total loss of FKBP12 in adult hearts compared with control animals. However, only the early embryonic deletion of FKBP12 (αMHC-Cre) resulted in an early-onset and progressive DCM, increased cardiac oxidative stress, altered expression of proteins associated with cardiac remodeling and disease, and sarcoplasmic reticulum Ca2+ leak. Our findings indicate that FKBP12 deficiency during early development results in cardiac remodeling and altered expression of DCM-associated proteins that lead to progressive DCM in adult hearts, thus suggesting a major role for FKBP12 in embryonic cardiac muscle.","PeriodicalId":54828,"journal":{"name":"Journal of General Physiology","volume":"157 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11633665/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142808340","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 does mitochondrial Ca2+ change during ischemia and reperfusion? Implications for activation of the permeability transition pore. 线粒体Ca2+在缺血和再灌注过程中是如何变化的？渗透过渡孔活化的意义。

IF 3.3 2区医学

Journal of General Physiology Pub Date : 2025-01-06 Epub Date: 2024-12-19 DOI: 10.1085/jgp.202313520

Elizabeth Murphy, David A Eisner

{"title":"How does mitochondrial Ca2+ change during ischemia and reperfusion? Implications for activation of the permeability transition pore.","authors":"Elizabeth Murphy, David A Eisner","doi":"10.1085/jgp.202313520","DOIUrl":"10.1085/jgp.202313520","url":null,"abstract":"Cardiac ischemia followed by reperfusion results in cardiac cell death, which has been attributed to an increase of mitochondrial Ca2+ concentration, resulting in activation of the mitochondrial permeability transition pore (PTP). Evaluating this hypothesis requires understanding of the mechanisms responsible for control of mitochondrial Ca2+ in physiological conditions and how they are altered during both ischemia and reperfusion. Ca2+ influx is thought to occur through the mitochondrial Ca2+ uniporter (MCU). However, with deletion of the MCU, an increase in mitochondrial Ca2+ still occurs, suggesting an alternative Ca2+ influx mechanism during ischemia. There is less certainty about the mechanisms responsible for Ca2+ efflux, with contributions from both Ca2+/H+ exchange and a Na+-dependent Ca2+ efflux pathway. The molecular details of both mechanisms are not fully resolved. We discuss this and the contributions of both pathways to the accumulation of mitochondrial Ca2+ during ischemia and reperfusion. We further discuss the role of mitochondrial Ca2+ in activation of the PTP.","PeriodicalId":54828,"journal":{"name":"Journal of General Physiology","volume":"157 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11657230/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142857070","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

Null method to estimate the maximal PA at subsaturating concentrations of agonist. 无效法估算激动剂亚饱和浓度下的最大 PA 值。

IF 3.3 2区医学

Journal of General Physiology Pub Date : 2025-01-06 Epub Date: 2024-11-25 DOI: 10.1085/jgp.202413644

Allison L Germann, Spencer R Pierce, Joe Henry Steinbach, Gustav Akk

{"title":"Null method to estimate the maximal PA at subsaturating concentrations of agonist.","authors":"Allison L Germann, Spencer R Pierce, Joe Henry Steinbach, Gustav Akk","doi":"10.1085/jgp.202413644","DOIUrl":"10.1085/jgp.202413644","url":null,"abstract":"The maximal probability of being in an active state (PA,max) is a measure of gating efficacy for a given agonist acting on a given receptor channel. In macroscopic electrophysiological recordings, PA,max is typically estimated by comparing the amplitude of the current response to a saturating concentration of a test agonist to that of a reference agonist with known PA. Here, we describe an approach to estimate the PA,max for low-efficacy agonists at subsaturating concentrations. In this approach, the amplitude of the response to a high-efficacy control agonist applied alone is compared with the amplitude of the response to a control agonist coapplied with the low-efficacy test agonist that binds to the same site(s). If the response to the combination is larger than the response to the control agonist alone, then the PA,max of the test agonist is greater than the PA of the control response. Conversely, if the response to the control agonist is reduced upon exposure to the test agonist, then the PA,max of the test agonist is smaller than the PA of the control response. The exact PA,max of the test agonist can be determined by testing its effect at different concentrations of the control agonist to estimate the PA at which the effect changes direction. The main advantage of this approach lies in the ability to use low, subsaturating concentrations of the test agonist. The model-based predictions are supported by observations from activation of heteromeric and homomeric GABAA receptors by combinations of high- and low-efficacy orthosteric agonists.","PeriodicalId":54828,"journal":{"name":"Journal of General Physiology","volume":"157 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11602654/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142710418","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 sodium channel mutant removes fast inactivation with the inactivation particle bound. 钠通道突变体在失活粒子结合的情况下消除了快速失活。

IF 3.3 2区医学

Journal of General Physiology Pub Date : 2025-01-06 Epub Date: 2024-11-27 DOI: 10.1085/jgp.202413667

Yichen Liu, Francisco Bezanilla

引用次数: 0

Intrinsic adaptive plasticity in mouse and human sensory neurons. 小鼠和人类感觉神经元的内在适应可塑性。

IF 3.3 2区医学

Journal of General Physiology Pub Date : 2025-01-06 Epub Date: 2024-12-17 DOI: 10.1085/jgp.202313488

Lisa A McIlvried, John Smith Del Rosario, Melanie Y Pullen, Andi Wangzhou, Tayler D Sheahan, Andrew J Shepherd, Richard A Slivicki, John A Lemen, Theodore J Price, Bryan A Copits, Robert W Gereau

{"title":"Intrinsic adaptive plasticity in mouse and human sensory neurons.","authors":"Lisa A McIlvried, John Smith Del Rosario, Melanie Y Pullen, Andi Wangzhou, Tayler D Sheahan, Andrew J Shepherd, Richard A Slivicki, John A Lemen, Theodore J Price, Bryan A Copits, Robert W Gereau","doi":"10.1085/jgp.202313488","DOIUrl":"10.1085/jgp.202313488","url":null,"abstract":"In response to changes in activity induced by environmental cues, neurons in the central nervous system undergo homeostatic plasticity to sustain overall network function during abrupt changes in synaptic strengths. Homeostatic plasticity involves changes in synaptic scaling and regulation of intrinsic excitability. Increases in spontaneous firing and excitability of sensory neurons are evident in some forms of chronic pain in animal models and human patients. However, whether mechanisms of homeostatic plasticity are engaged in sensory neurons of the peripheral nervous system (PNS) is unknown. Here, we show that sustained depolarization (induced by 24-h incubation in 30 mM KCl) induces compensatory changes that decrease the excitability of mouse and human sensory neurons without directly opposing membrane depolarization. Voltage-clamp recordings show that sustained depolarization produces no significant alteration in voltage-gated potassium currents, but a robust reduction in voltage-gated sodium currents, likely contributing to the overall decrease in neuronal excitability. The compensatory decrease in neuronal excitability and reduction in voltage-gated sodium currents reversed completely following a 24-h recovery period in a normal medium. Similar adaptive changes were not observed in response to 24 h of sustained action potential firing induced by optogenetic stimulation at 1 Hz, indicating the need for prolonged depolarization to drive engagement of this adaptive mechanism in sensory neurons. Our findings show that mouse and human sensory neurons are capable of engaging adaptive mechanisms to regulate intrinsic excitability in response to sustained depolarization in a manner similar to that described in neurons in the central nervous system.","PeriodicalId":54828,"journal":{"name":"Journal of General Physiology","volume":"157 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11651306/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142840324","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: Toward an understanding of the structural basis of allostery in muscarinic acetylcholine receptors. 更正：对毒蕈碱乙酰胆碱受体变构的结构基础的理解。

IF 3.3 2区医学

Journal of General Physiology Pub Date : 2025-01-06 Epub Date: 2024-12-19 DOI: 10.1085/jgp.20171197912022024c

Wessel A C Burger, Patrick M Sexton, Arthur Christopoulos, David M Thal

引用次数: 0

Time-dependent effect of FKBP12 loss in the development of dilated cardiomyopathy. FKBP12缺失在扩张型心肌病发展中的时间依赖性作用。

IF 3.3 2区医学

Journal of General Physiology Pub Date : 2025-01-06 Epub Date: 2024-12-12 DOI: 10.1085/jgp.202413673

Joan A Chan, Michelle L Munro

引用次数: 0