The Journal of General Physiology最新文献_第5页

A two-step docking site model predicting different short-term synaptic plasticity patterns. 预测不同短期突触可塑性模式的两步对接位点模型。

IF 3.8

The Journal of General Physiology Pub Date : 2018-08-06 Epub Date: 2018-06-27 DOI: 10.1085/jgp.201812072

Camila Pulido, Alain Marty

{"title":"A two-step docking site model predicting different short-term synaptic plasticity patterns.","authors":"Camila Pulido, Alain Marty","doi":"10.1085/jgp.201812072","DOIUrl":"https://doi.org/10.1085/jgp.201812072","url":null,"abstract":"The strength of synaptic transmission varies during trains of presynaptic action potentials, notably because of the depletion of synaptic vesicles available for release. It has remained unclear why some synapses display depression over time, whereas others facilitate or show a facilitation and depression sequence. Here we compare the predictions of various synaptic models assuming that several docking/release sites are acting in parallel. These models show variation of docking site occupancy during trains of action potentials due to vesicular release and site replenishment, which give rise to changes in synaptic strength. To conform with recent studies, we assume an initial docking site occupancy of <1, thus permitting site occupancy to increase during action potential trains and facilitation to occur. We consider both a standard one-step model and a more elaborate model that assumes a predocked state (two-step model). Whereas the one-step model predicts monotonic changes of synaptic strength during a train, the two-step model allows nonmonotonic changes, including the often-observed facilitation/depression sequence. Both models predict a partitioning of parameter space between initially depressing and facilitating synapses. Using data obtained from interneuron synapses in the cerebellum, we demonstrate an unusual form of depression/facilitation sequence for very high release probability after prolonged depolarization-induced transmitter release. These results indicate a depletion of predocked vesicles in the two-step model. By permitting docking site occupancy to be <1 at rest, and by incorporating a separate predocked state, we reveal that docking site models can be expanded to mimic the large variety of time-dependent changes of synaptic strength that have been observed during action potential trains. Furthermore, the two-step model provides an effective framework to identify the specific mechanisms responsible for short-term changes in synaptic strength.","PeriodicalId":173753,"journal":{"name":"The Journal of General Physiology","volume":" ","pages":"1107-1124"},"PeriodicalIF":3.8,"publicationDate":"2018-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1085/jgp.201812072","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36263233","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 14

Heat-resistant action potentials require TTX-resistant sodium channels Na_V1.8 and Na_V1.9. 耐热动作电位需要耐ttx钠通道NaV1.8和NaV1.9。

IF 3.8

The Journal of General Physiology Pub Date : 2018-08-06 Epub Date: 2018-07-03 DOI: 10.1085/jgp.201711786

Filip Touska, Brian Turnquist, Viktorie Vlachova, Peter W Reeh, Andreas Leffler, Katharina Zimmermann

{"title":"Heat-resistant action potentials require TTX-resistant sodium channels NaV1.8 and NaV1.9.","authors":"Filip Touska, Brian Turnquist, Viktorie Vlachova, Peter W Reeh, Andreas Leffler, Katharina Zimmermann","doi":"10.1085/jgp.201711786","DOIUrl":"https://doi.org/10.1085/jgp.201711786","url":null,"abstract":"Damage-sensing nociceptors in the skin provide an indispensable protective function thanks to their specialized ability to detect and transmit hot temperatures that would block or inflict irreversible damage in other mammalian neurons. Here we show that the exceptional capacity of skin C-fiber nociceptors to encode noxiously hot temperatures depends on two tetrodotoxin (TTX)-resistant sodium channel α-subunits: NaV1.8 and NaV1.9. We demonstrate that NaV1.9, which is commonly considered an amplifier of subthreshold depolarizations at 20°C, undergoes a large gain of function when temperatures rise to the pain threshold. We also show that this gain of function renders NaV1.9 capable of generating action potentials with a clear inflection point and positive overshoot. In the skin, heat-resistant nociceptors appear as two distinct types with unique and possibly specialized features: one is blocked by TTX and relies on NaV1.9, and the second type is insensitive to TTX and composed of both NaV1.8 and NaV1.9. Independent of rapidly gated TTX-sensitive NaV channels that form the action potential at pain threshold, NaV1.8 is required in all heat-resistant nociceptors to encode temperatures higher than ∼46°C, whereas NaV1.9 is crucial for shaping the action potential upstroke and keeping the NaV1.8 voltage threshold within reach.","PeriodicalId":173753,"journal":{"name":"The Journal of General Physiology","volume":" ","pages":"1125-1144"},"PeriodicalIF":3.8,"publicationDate":"2018-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1085/jgp.201711786","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36282455","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 14

No voltage change at skeletal muscle SR membrane during Ca²⁺ release-just Mermaids on acid. Ca2+释放过程中骨骼肌SR膜无电压变化，只是酸上的美人鱼。

IF 3.8

The Journal of General Physiology Pub Date : 2018-08-06 Epub Date: 2018-07-03 DOI: 10.1085/jgp.201812084

Werner Melzer

{"title":"No voltage change at skeletal muscle SR membrane during Ca2+ release-just Mermaids on acid.","authors":"Werner Melzer","doi":"10.1085/jgp.201812084","DOIUrl":"https://doi.org/10.1085/jgp.201812084","url":null,"abstract":"Calcium ions control multiple physiological functions by binding to extracellular and intracellular targets. One of the best-studied Ca2+-dependent functions is contraction of smooth and striated muscle tissue, which results from Ca2+ ligation to calmodulin and troponin C, respectively. Ca2+ signaling typically involves flux of the ion across membranes via specifically gated channel proteins. Because calcium ions are charged, they possess the ability to generate changes in the respective transmembrane voltage. Ca2+-dependent voltage alterations of the surface membrane are easily measured using microelectrodes. A well-known example is the characteristic plateau phase of the action potential in cardiac ventricular cells that results from the opening of voltage-gated L-type Ca2+ channels. Ca2+ ions are also released from intracellular storage compartments in many cells, but these membranes are not accessible to direct voltage recording with microelectrodes. In muscle, for example, release of Ca2+ from the sarcoplasmic reticulum (SR) to the myoplasm constitutes a flux that is considerably larger than the entry flux from the extracellular space. Whether this flux is accompanied by a voltage change across the SR membrane is an obvious question of mechanistic importance and has been the subject of many investigations. Because the tiny spaces enclosed by the SR membrane are inaccessible to microelectrodes, alternative methods have to be applied. In a study by Sanchez et al. (2018. J. Gen. Physiol. https://doi.org/10.1085/jgp.201812035) in this issue, modern confocal light microscopy and genetically encoded voltage probes targeted to the SR were applied in a new approach to search for changes in the membrane potential of the SR during Ca2+ release.","PeriodicalId":173753,"journal":{"name":"The Journal of General Physiology","volume":" ","pages":"1055-1058"},"PeriodicalIF":3.8,"publicationDate":"2018-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1085/jgp.201812084","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36282453","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 3

Bridging the gap toward understanding short-term synaptic plasticity. 弥合理解短期突触可塑性的差距。

IF 3.8

The Journal of General Physiology Pub Date : 2018-08-06 Epub Date: 2018-07-11 DOI: 10.1085/jgp.201812166

Caitlin Sedwick

引用次数: 0

Influences: Sodium channel excitement. 影响:钠离子通道兴奋。

IF 3.8

The Journal of General Physiology Pub Date : 2018-08-06 Epub Date: 2018-07-20 DOI: 10.1085/jgp.201812151

Gail Mandel

引用次数: 1

Structure, function, and allosteric modulation of NMDA receptors. NMDA受体的结构、功能和变构调节。

IF 3.8

The Journal of General Physiology Pub Date : 2018-08-06 Epub Date: 2018-07-23 DOI: 10.1085/jgp.201812032

Kasper B Hansen, Feng Yi, Riley E Perszyk, Hiro Furukawa, Lonnie P Wollmuth, Alasdair J Gibb, Stephen F Traynelis

{"title":"Structure, function, and allosteric modulation of NMDA receptors.","authors":"Kasper B Hansen, Feng Yi, Riley E Perszyk, Hiro Furukawa, Lonnie P Wollmuth, Alasdair J Gibb, Stephen F Traynelis","doi":"10.1085/jgp.201812032","DOIUrl":"https://doi.org/10.1085/jgp.201812032","url":null,"abstract":"NMDA-type glutamate receptors are ligand-gated ion channels that mediate a Ca2+-permeable component of excitatory neurotransmission in the central nervous system (CNS). They are expressed throughout the CNS and play key physiological roles in synaptic function, such as synaptic plasticity, learning, and memory. NMDA receptors are also implicated in the pathophysiology of several CNS disorders and more recently have been identified as a locus for disease-associated genomic variation. NMDA receptors exist as a diverse array of subtypes formed by variation in assembly of seven subunits (GluN1, GluN2A-D, and GluN3A-B) into tetrameric receptor complexes. These NMDA receptor subtypes show unique structural features that account for their distinct functional and pharmacological properties allowing precise tuning of their physiological roles. Here, we review the relationship between NMDA receptor structure and function with an emphasis on emerging atomic resolution structures, which begin to explain unique features of this receptor.","PeriodicalId":173753,"journal":{"name":"The Journal of General Physiology","volume":" ","pages":"1081-1105"},"PeriodicalIF":3.8,"publicationDate":"2018-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1085/jgp.201812032","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36337879","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 319

Biaryl sulfonamide motifs up- or down-regulate ion channel activity by activating voltage sensors. 联芳基磺胺基序通过激活电压传感器来上调或下调离子通道活性。

IF 3.8

The Journal of General Physiology Pub Date : 2018-08-06 Epub Date: 2018-07-12 DOI: 10.1085/jgp.201711942

Sara I Liin, Per-Eric Lund, Johan E Larsson, Johan Brask, Björn Wallner, Fredrik Elinder

{"title":"Biaryl sulfonamide motifs up- or down-regulate ion channel activity by activating voltage sensors.","authors":"Sara I Liin, Per-Eric Lund, Johan E Larsson, Johan Brask, Björn Wallner, Fredrik Elinder","doi":"10.1085/jgp.201711942","DOIUrl":"https://doi.org/10.1085/jgp.201711942","url":null,"abstract":"Voltage-gated ion channels are key molecules for the generation of cellular electrical excitability. Many pharmaceutical drugs target these channels by blocking their ion-conducting pore, but in many cases, channel-opening compounds would be more beneficial. Here, to search for new channel-opening compounds, we screen 18,000 compounds with high-throughput patch-clamp technology and find several potassium-channel openers that share a distinct biaryl-sulfonamide motif. Our data suggest that the negatively charged variants of these compounds bind to the top of the voltage-sensor domain, between transmembrane segments 3 and 4, to open the channel. Although we show here that biaryl-sulfonamide compounds open a potassium channel, they have also been reported to block sodium and calcium channels. However, because they inactivate voltage-gated sodium channels by promoting activation of one voltage sensor, we suggest that, despite different effects on the channel gates, the biaryl-sulfonamide motif is a general ion-channel activator motif. Because these compounds block action potential-generating sodium and calcium channels and open an action potential-dampening potassium channel, they should have a high propensity to reduce excitability. This opens up the possibility to build new excitability-reducing pharmaceutical drugs from the biaryl-sulfonamide scaffold.","PeriodicalId":173753,"journal":{"name":"The Journal of General Physiology","volume":" ","pages":"1215-1230"},"PeriodicalIF":3.8,"publicationDate":"2018-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1085/jgp.201711942","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36308005","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 8

Mechanistic complexity of contractile dysfunction in hypertrophic cardiomyopathy. 肥厚性心肌病收缩功能障碍的机制复杂性。

IF 3.8

The Journal of General Physiology Pub Date : 2018-08-06 Epub Date: 2018-07-23 DOI: 10.1085/jgp.201812091

Michael Regnier

引用次数: 2

Calnexin revealed as an ether-a-go-go chaperone by getting mutant worms up and going. 钙连蛋白被发现是一种以太-a-go-go的伴侣，它能让突变的蠕虫活跃起来。

IF 3.8

The Journal of General Physiology Pub Date : 2018-08-06 Epub Date: 2018-07-03 DOI: 10.1085/jgp.201812068

Jonathan T Pierce

{"title":"Calnexin revealed as an ether-a-go-go chaperone by getting mutant worms up and going.","authors":"Jonathan T Pierce","doi":"10.1085/jgp.201812068","DOIUrl":"https://doi.org/10.1085/jgp.201812068","url":null,"abstract":"The role of ion channels in cell excitability was first revealed in a series of voltage clamp experiments by Hodgkin and Huxley in the 1950s. However, it was not until the 1970s that patch-clamp recording ushered in a revolution that allowed physiologists to witness how ion channels flicker open and closed at angstrom scale and with microsecond resolution. The unexpectedly tight seal made by the patch pipette in the whole-cell configuration later allowed molecular biologists to suck up the insides of identified cells to unveil their unique molecular contents. By refining these techniques, researchers have scrutinized the surface and contents of excitable cells in detail over the past few decades. However, these powerful approaches do not discern which molecules are responsible for the dynamic control of the genesis, abundance, and subcellular localization of ion channels. In this dark territory, teams of unknown and poorly understood molecules guide specific ion channels through translation, folding, and modification, and then they shuttle them toward and away from distinct membrane domains via different subcellular routes. A central challenge in understanding these processes is the likelihood that these diverse regulatory molecules may be specific to ion channel subtypes, cell types, and circumstance. In work described in this issue, Bai et al. (2018. J. Gen. Physiol. https://doi.org/10.1085/jgp.201812025) begin to shed light on the biogenesis of UNC-103, a K+ channel found in Caenorhabditis elegans.","PeriodicalId":173753,"journal":{"name":"The Journal of General Physiology","volume":" ","pages":"1059-1061"},"PeriodicalIF":3.8,"publicationDate":"2018-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1085/jgp.201812068","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36282452","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Carriers, exchangers, and cotransporters in the first 100 years of the Journal of General Physiology. 《普通生理学杂志》前100年的载体、交换体和共转运体。

IF 3.8

The Journal of General Physiology Pub Date : 2018-08-06 Epub Date: 2018-07-20 DOI: 10.1085/jgp.201812078

Michael L Jennings

{"title":"Carriers, exchangers, and cotransporters in the first 100 years of the Journal of General Physiology.","authors":"Michael L Jennings","doi":"10.1085/jgp.201812078","DOIUrl":"https://doi.org/10.1085/jgp.201812078","url":null,"abstract":"Transporters, pumps, and channels are proteins that catalyze the movement of solutes across membranes. The single-solute carriers, coupled exchangers, and coupled cotransporters that are collectively known as transporters are distinct from conductive ion channels, water channels, and ATP-hydrolyzing pumps. The main conceptual framework for studying transporter mechanisms is the alternating access model, which comprises substrate binding and release events on each side of the permeability barrier and translocation events involving conformational changes between inward-facing and outward-facing conformational states. In 1948, the Journal of General Physiology began to publish work that focused on the erythrocyte glucose transporter—the first transporter to be characterized kinetically—followed by articles on the rates, stoichiometries, asymmetries, voltage dependences, and regulation of coupled exchangers and cotransporters beginning in the 1960s. After the dawn of cDNA cloning and sequencing in the 1980s, heterologous expression systems and site-directed mutagenesis allowed identification of the functional roles of specific amino acid residues. In the past two decades, structures of transport proteins have made it possible to propose specific models for transporter function at the molecular level. Here, we review the contribution of JGP articles to our current understanding of solute transporter mechanisms. Whether the topic has been kinetics, energetics, regulation, mutagenesis, or structure-based modeling, a common feature of these articles has been a quantitative, mechanistic approach, leading to lasting insights into the functions of transporters.","PeriodicalId":173753,"journal":{"name":"The Journal of General Physiology","volume":" ","pages":"1063-1080"},"PeriodicalIF":3.8,"publicationDate":"2018-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1085/jgp.201812078","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36330201","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 6