Journal of General Physiology最新文献_第8页

Connecting the dots on connexin function. 连接连接蛋白功能的点。

IF 3.3 2区医学

Journal of General Physiology Pub Date : 2024-11-04 Epub Date: 2024-10-14 DOI: 10.1085/jgp.202413675

Ben Short

引用次数: 0

Light induces a rapid increase in cAMP and activates PKA in rod outer segments of the frog retina. 光能诱导 cAMP 快速增加，并激活蛙视网膜视杆细胞外节的 PKA。

IF 3.3 2区医学

Journal of General Physiology Pub Date : 2024-11-04 Epub Date: 2024-10-22 DOI: 10.1085/jgp.202313530

Olga Chernyshkova, Natalia Erofeeva, Darya Meshalkina, Anna Balykina, Stepan Gambaryan, Michael Belyakov, Michael Firsov

{"title":"Light induces a rapid increase in cAMP and activates PKA in rod outer segments of the frog retina.","authors":"Olga Chernyshkova, Natalia Erofeeva, Darya Meshalkina, Anna Balykina, Stepan Gambaryan, Michael Belyakov, Michael Firsov","doi":"10.1085/jgp.202313530","DOIUrl":"10.1085/jgp.202313530","url":null,"abstract":"The phototransduction cascade enables the photoreceptor to detect light over a wide range of intensities without saturation. The main second messenger of the cascade is cGMP and the primary regulatory mechanism is calcium feedback. However, some experimental data suggest that cAMP may also play a role in regulating the phototransduction cascade, but this would require changes in cAMP on a time scale of seconds. Currently, there is a lack of data on the dynamics of changes in intracellular cAMP levels on this timescale. This is largely due to the specificity of the sensory modality of photoreceptors, which makes it practically impossible to use conventional experimental approaches based on fluorescence methods. In this study, we employed the method of rapid cryofixation of retinal samples after light stimulation and subsequent isolation of outer segment preparations. The study employed highly sensitive metabolomics approaches to measure levels of cAMP. Additionally, PKA activity was measured in the samples using a western blot. The results indicate that when exposed to near-saturating but still moderate light, cAMP levels increase transiently within the first second and then return to pre-stimulus levels. The increase in cAMP activates PKA, resulting in the phosphorylation of PKA-specific substrates in frog retinal outer segments.","PeriodicalId":54828,"journal":{"name":"Journal of General Physiology","volume":"156 11","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11498274/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142481289","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

What happened to the pursuit of truth? 追求真理怎么了？

IF 3.3 2区医学

Journal of General Physiology Pub Date : 2024-11-04 Epub Date: 2024-10-23 DOI: 10.1085/jgp.202413672

Eve Marder

引用次数: 0

Modeling the mechanism of Ca2+ release in skeletal muscle by DHPRs easing inhibition at RyR I1-sites. 通过 DHPRs 缓解 RyR I1 位点的抑制作用，模拟骨骼肌中 Ca2+ 释放的机制。

IF 3.3 2区医学

Journal of General Physiology Pub Date : 2024-10-07 Epub Date: 2024-09-04 DOI: 10.1085/jgp.202213113

D George Stephenson

{"title":"Modeling the mechanism of Ca2+ release in skeletal muscle by DHPRs easing inhibition at RyR I1-sites.","authors":"D George Stephenson","doi":"10.1085/jgp.202213113","DOIUrl":"10.1085/jgp.202213113","url":null,"abstract":"Ca2+ release from the sarcoplasmic reticulum (SR) plays a central role in excitation-contraction coupling (ECC) in skeletal muscles. However, the mechanism by which activation of the voltage-sensors/dihydropyridine receptors (DHPRs) in the membrane of the transverse tubular system leads to activation of the Ca2+-release channels/ryanodine receptors (RyRs) in the SR is not fully understood. Recent observations showing that a very small Ca2+ leak through RyR1s in mammalian skeletal muscle can markedly raise the background [Ca2+] in the junctional space (JS) above the Ca2+ level in the bulk of the cytosol indicate that there is a diffusional barrier between the JS and the cytosol at large. Here, I use a mathematical model to explore the hypothesis that a sudden rise in Ca2+ leak through DHPR-coupled RyR1s, caused by reduced inhibition at the RyR1 Ca2+/Mg2+ inhibitory I1-sites when the associated DHPRs are activated, is sufficient to enable synchronized responses that trigger a regenerative rise of Ca2+ release that remains under voltage control. In this way, the characteristic response to Ca2+ of RyR channels is key not only for the Ca2+ release mechanism in cardiac muscle and other tissues, but also for the DHPR-dependent Ca2+ release in skeletal muscle.","PeriodicalId":54828,"journal":{"name":"Journal of General Physiology","volume":"156 10","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11390858/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142127393","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

Grammotoxin increases its toxic behavior. 革兰氏毒素会增加其毒性。

IF 3.3 2区医学

Journal of General Physiology Pub Date : 2024-10-07 Epub Date: 2024-09-25 DOI: 10.1085/jgp.202413665

Ben Short

引用次数: 0

Fluorescence labeling strategies for cell surface expression of TRPV1. 细胞表面表达 TRPV1 的荧光标记策略。

IF 3.3 2区医学

Journal of General Physiology Pub Date : 2024-10-07 Epub Date: 2024-08-20 DOI: 10.1085/jgp.202313523

Taylor M Mott, Grace C Wulffraat, Alex J Eddins, Ryan A Mehl, Eric N Senning

{"title":"Fluorescence labeling strategies for cell surface expression of TRPV1.","authors":"Taylor M Mott, Grace C Wulffraat, Alex J Eddins, Ryan A Mehl, Eric N Senning","doi":"10.1085/jgp.202313523","DOIUrl":"10.1085/jgp.202313523","url":null,"abstract":"Regulation of ion channel expression on the plasma membrane is a major determinant of neuronal excitability, and identifying the underlying mechanisms of this expression is critical to our understanding of neurons. Here, we present two orthogonal strategies to label extracellular sites of the ion channel TRPV1 that minimally perturb its function. We use the amber codon suppression technique to introduce a non-canonical amino acid (ncAA) with tetrazine click chemistry, compatible with a trans-cyclooctene coupled fluorescent dye. Additionally, by inserting the circularly permutated HaloTag (cpHaloTag) in an extracellular loop of TRPV1, we can incorporate a fluorescent dye of our choosing. Optimization of ncAA insertion sites was accomplished by screening residue positions between the S1 and S2 transmembrane domains with elevated missense variants in the human population. We identified T468 as a rapid labeling site (∼5 min) based on functional and biochemical assays in HEK293T/17 cells. Through adapting linker lengths and backbone placement of cpHaloTag on the extracellular side of TRPV1, we generated a fully functional channel construct, TRPV1exCellHalo, with intact wild-type gating properties. We used TRPV1exCellHalo in a single molecule experiment to track TRPV1 on the cell surface and validate studies that show decreased mobility of the channel upon activation. The application of these extracellular label TRPV1 (exCellTRPV1) constructs to track surface localization of the channel will shed significant light on the mechanisms regulating its expression and provide a general scheme to introduce similar modifications to other cell surface receptors.","PeriodicalId":54828,"journal":{"name":"Journal of General Physiology","volume":"156 10","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11338283/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142005960","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

Rad protein: An essential player in L-type Ca2+ channel localization and modulation in cardiomyocytes. Rad 蛋白：心肌细胞中 L 型 Ca2+ 通道定位和调节的重要参与者。

IF 3.3 2区医学

Journal of General Physiology Pub Date : 2024-10-07 Epub Date: 2024-08-22 DOI: 10.1085/jgp.202413629

Cherrie H T Kong, Eef Dries

引用次数: 0

Ion channels of cold transduction and transmission. 冷传导和传输的离子通道。

IF 3.3 2区医学

Journal of General Physiology Pub Date : 2024-10-07 Epub Date: 2024-07-25 DOI: 10.1085/jgp.202313529

Cheyanne M Lewis, Theanne N Griffith

{"title":"Ion channels of cold transduction and transmission.","authors":"Cheyanne M Lewis, Theanne N Griffith","doi":"10.1085/jgp.202313529","DOIUrl":"10.1085/jgp.202313529","url":null,"abstract":"Thermosensation requires the activation of a unique collection of ion channels and receptors that work in concert to transmit thermal information. It is widely accepted that transient receptor potential melastatin 8 (TRPM8) activation is required for normal cold sensing; however, recent studies have illuminated major roles for other ion channels in this important somatic sensation. In addition to TRPM8, other TRP channels have been reported to contribute to cold transduction mechanisms in diverse sensory neuron populations, with both leak- and voltage-gated channels being identified for their role in the transmission of cold signals. Whether the same channels that contribute to physiological cold sensing also mediate noxious cold signaling remains unclear; however, recent work has found a conserved role for the kainite receptor, GluK2, in noxious cold sensing across species. Additionally, cold-sensing neurons likely engage in functional crosstalk with nociceptors to give rise to cold pain. This Review will provide an update on our understanding of the relationship between various ion channels in the transduction and transmission of cold and highlight areas where further investigation is required.","PeriodicalId":54828,"journal":{"name":"Journal of General Physiology","volume":"156 10","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11273221/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141762722","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

Novel cardiac myosin inhibitor for hypertrophic cardiomyopathy. 治疗肥厚型心肌病的新型心肌酶抑制剂。

IF 3.3 2区医学

Journal of General Physiology Pub Date : 2024-10-07 Epub Date: 2024-08-12 DOI: 10.1085/jgp.202413640

Danuta Szczesna-Cordary

引用次数: 0

Mechanisms of a novel regulatory light chain-dependent cardiac myosin inhibitor. 新型调节轻链依赖性心肌肌球蛋白抑制剂的作用机制

IF 3.3 2区医学

Journal of General Physiology Pub Date : 2024-10-07 Epub Date: 2024-07-31 DOI: 10.1085/jgp.202313503

Kristina Kooiker, Qing-Fen Gan, Ming Yu, Na Sa, Saffie Mohran, Yuanhua Cheng, Galina Flint, Stephanie Neys, Chengqian Gao, Devin Nissen, Tim McMillen, Anthony Asencio, Weikang Ma, Thomas C Irving, Farid Moussavi-Harami, Michael Regnier

{"title":"Mechanisms of a novel regulatory light chain-dependent cardiac myosin inhibitor.","authors":"Kristina Kooiker, Qing-Fen Gan, Ming Yu, Na Sa, Saffie Mohran, Yuanhua Cheng, Galina Flint, Stephanie Neys, Chengqian Gao, Devin Nissen, Tim McMillen, Anthony Asencio, Weikang Ma, Thomas C Irving, Farid Moussavi-Harami, Michael Regnier","doi":"10.1085/jgp.202313503","DOIUrl":"10.1085/jgp.202313503","url":null,"abstract":"Hypertrophic cardiomyopathy (HCM) is a genetic disease of the heart characterized by thickening of the left ventricle (LV), hypercontractility, and impaired relaxation. HCM is caused primarily by heritable mutations in sarcomeric proteins, such as β myosin heavy chain. Until recently, medications in clinical use for HCM did not directly target the underlying contractile changes in the sarcomere. Here, we investigate a novel small molecule, RLC-1, identified in a bovine cardiac myofibril high-throughput screen. RLC-1 is highly dependent on the presence of a regulatory light chain to bind to cardiac myosin and modulate its ATPase activity. In demembranated rat LV trabeculae, RLC-1 decreased maximal Ca2+-activated force and Ca2+ sensitivity of force, while it increased the submaximal rate constant for tension redevelopment. In myofibrils isolated from rat LV, both maximal and submaximal Ca2+-activated force are reduced by nearly 50%. Additionally, the fast and slow phases of relaxation were approximately twice as fast as DMSO controls, and the duration of the slow phase was shorter. Structurally, x-ray diffraction studies showed that RLC-1 moved myosin heads away from the thick filament backbone and decreased the order of myosin heads, which is different from other myosin inhibitors. In intact trabeculae and isolated cardiomyocytes, RLC-1 treatment resulted in decreased peak twitch magnitude and faster activation and relaxation kinetics. In conclusion, RLC-1 accelerated kinetics and decreased force production in the demembranated tissue, intact tissue, and intact whole cells, resulting in a smaller cardiac twitch, which could improve the underlying contractile changes associated with HCM.","PeriodicalId":54828,"journal":{"name":"Journal of General Physiology","volume":"156 10","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11291911/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141857225","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