The Journal of General Physiology最新文献

Cannabidiol potentiates hyperpolarization-activated cyclic nucleotide-gated (HCN4) channels. 大麻二酚能增强超极化激活的环核苷酸门控（HCN4）通道。

The Journal of General Physiology Pub Date : 2024-04-23 DOI: 10.1085/jgp.202313505

D. Page, Peter C Ruben

{"title":"Cannabidiol potentiates hyperpolarization-activated cyclic nucleotide-gated (HCN4) channels.","authors":"D. Page, Peter C Ruben","doi":"10.1085/jgp.202313505","DOIUrl":"https://doi.org/10.1085/jgp.202313505","url":null,"abstract":"Cannabidiol (CBD), the main non-psychotropic phytocannabinoid produced by the Cannabis sativa plant, blocks a variety of cardiac ion channels. We aimed to identify whether CBD regulated the cardiac pacemaker channel or the hyperpolarization-activated cyclic nucleotide-gated channel (HCN4). HCN4 channels are important for the generation of the action potential in the sinoatrial node of the heart and increased heart rate in response to β-adrenergic stimulation. HCN4 channels were expressed in HEK 293T cells, and the effect of CBD application was examined using a whole-cell patch clamp. We found that CBD depolarized the V1/2 of activation in holo-HCN4 channels, with an EC50 of 1.6 µM, without changing the current density. CBD also sped activation kinetics by approximately threefold. CBD potentiation of HCN4 channels occurred via binding to the closed state of the channel. We found that CBD's mechanism of action was distinct from cAMP, as CBD also potentiated apo-HCN4 channels. The addition of an exogenous PIP2 analog did not alter the ability of CBD to potentiate HCN4 channels, suggesting that CBD also acts using a unique mechanism from the known HCN4 potentiator PIP2. Lastly, to gain insight into CBD's mechanism of action, computational modeling and targeted mutagenesis were used to predict that CBD binds to a lipid-binding pocket at the C-terminus of the voltage sensor. CBD represents the first FDA-approved drug to potentiate HCN4 channels, and our findings suggest a novel starting point for drug development targeting HCN4 channels.","PeriodicalId":173753,"journal":{"name":"The Journal of General Physiology","volume":"35 11","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140670942","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Mutation in pore-helix modulates interplay between filter gate and Ba2+ block in a Kcv channel pore 孔螺旋的突变可调节 Kcv 通道孔中滤波门和 Ba2+阻断之间的相互作用

The Journal of General Physiology Pub Date : 2024-04-23 DOI: 10.1085/jgp.202313514

Noel Tewes, Beatrice Kubitzki, Flandrit Bytyqi, Nikola Metko, Sebastian Mach, Gerhard Thiel, O. Rauh

引用次数: 0

Correction: A controversial issue: Can mitochondria modulate cytosolic calcium and contraction of skeletal muscle fibers? 更正:一个有争议的问题:线粒体能否调节胞质钙和骨骼肌纤维的收缩?

IF 3.8

The Journal of General Physiology Pub Date : 2022-10-03 Epub Date: 2022-09-19 DOI: 10.1085/jgp.20221316709092022c

Carlo Reggiani, Lorenzo Marcucci

{"title":"Correction: A controversial issue: Can mitochondria modulate cytosolic calcium and contraction of skeletal muscle fibers?","authors":"Carlo Reggiani, Lorenzo Marcucci","doi":"10.1085/jgp.20221316709092022c","DOIUrl":"https://doi.org/10.1085/jgp.20221316709092022c","url":null,"abstract":"In the first decade of the new century, the free Ca 2+ indicators were applied also in living adult muscle fibers and opened a new per-spective. Lännergren et al. (2001) using Rhod2 reported calcium accumulation in mitochondria during prolonged contractile activity in Xenopus fibers but not in mouse fast flexor digitorum brevis (FDB) fibers. 2 yr later, Bruton et al. (2003) measuring cytosolic calcium with Indo-1 and mitochondrial calcium with Rhod2 in mouse soleus and EDL fibers observed, after fatiguing stimulation, an increase of mitochondrial matrix calcium in both muscles. The absence of mitochondrial calcium uptake during tetanic stimulation was fur-ther confirmed on FDB fibers loaded with Rhod2 (Aydin et al., 2009). In contrast, cameleon probes targeted to mitochondria produced clear-cut evidence of transient increases of mitochondrial Ca 2+ concentration in electrically stimulated murine muscles with consistent results in tibialis anterior fibers in situ (Rudolf and in isolated FDB fibers (Scorzeto The matrix-free Ca 2+ concentration follows closely cytosolic-free Ca 2+ variations, even during a single twitch, although with a somewhat different kinetics. A fast rise phase was followed by a slow decrease, and this allowed the integration of the signals coming from repeated stimulations/action potentials. Importantly, the time scale of the metabolic activation triggered by calcium is much faster compared to the activation induced by ADP and creatine which implies energy depletion. Thus, calcium-activation","PeriodicalId":173753,"journal":{"name":"The Journal of General Physiology","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2022-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9516837/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40368706","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

Acute exposure to extracellular BTP2 does not inhibit Ca2+ release during EC coupling in intact skeletal muscle fibers. 急性暴露于细胞外BTP2不会抑制完整骨骼肌纤维EC偶联期间Ca2+的释放。

IF 3.8

The Journal of General Physiology Pub Date : 2022-09-05 Epub Date: 2021-12-15 DOI: 10.1085/jgp.202112976

Lan Wei-LaPierre, Linda Groom, Robert T Dirksen

{"title":"Acute exposure to extracellular BTP2 does not inhibit Ca2+ release during EC coupling in intact skeletal muscle fibers.","authors":"Lan Wei-LaPierre, Linda Groom, Robert T Dirksen","doi":"10.1085/jgp.202112976","DOIUrl":"https://doi.org/10.1085/jgp.202112976","url":null,"abstract":"The inhibitor of store-operated Ca2+ entry (SOCE) BTP2 was reported to inhibit ryanodine receptor Ca2+ leak and electrically evoked Ca2+ release from the sarcoplasmic reticulum when introduced into mechanically skinned muscle fibers. However, it is unclear how effects of intracellular application of a highly lipophilic drug like BTP2 on Ca2+ release during excitation-contraction (EC) coupling compare with extracellular exposure in intact muscle fibers. Here, we address this question by quantifying the effect of short- and long-term exposure to 10 and 20 µM BTP2 on the magnitude and kinetics of electrically evoked Ca2+ release in intact mouse flexor digitorum brevis muscle fibers. Our results demonstrate that neither the magnitude nor the kinetics of electrically evoked Ca2+ release evoked during repetitive electrical stimulation were altered by brief exposure (2 min) to either BTP2 concentration. However, BTP2 did reduce the magnitude of electrically evoked Ca2+ release in intact fibers when applied extracellularly for a prolonged period of time (30 min at 10 µM or 10 min at 20 µM), consistent with slow diffusion of the lipophilic drug across the plasma membrane. Together, these results indicate that the time course and impact of BTP2 on Ca2+ release during EC coupling in skeletal muscle depends strongly on whether the drug is applied intracellularly or extracellularly. Further, these results demonstrate that electrically evoked Ca2+ release in intact muscle fibers is unaltered by extracellular application of 10 µM BTP2 for <25 min, validating this use to assess the role of SOCE in the absence of an effect on EC coupling.","PeriodicalId":173753,"journal":{"name":"The Journal of General Physiology","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2022-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/2b/9a/JGP_202112976.PMC8679509.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39728003","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

Junctophilins 1, 2, and 3 all support voltage-induced Ca2+ release despite considerable divergence. 亲结膜蛋白1、2和3都支持电压诱导的Ca2+释放，尽管存在相当大的差异。

IF 3.8

The Journal of General Physiology Pub Date : 2022-09-05 Epub Date: 2022-01-28 DOI: 10.1085/jgp.202113024

Stefano Perni, Kurt Beam

{"title":"Junctophilins 1, 2, and 3 all support voltage-induced Ca2+ release despite considerable divergence.","authors":"Stefano Perni, Kurt Beam","doi":"10.1085/jgp.202113024","DOIUrl":"https://doi.org/10.1085/jgp.202113024","url":null,"abstract":"In skeletal muscle, depolarization of the plasma membrane (PM) causes conformational changes of the calcium channel CaV1.1 that then activate RYR1 to release calcium from the SR. Being independent of extracellular calcium entry, this process is termed voltage-induced calcium release. In skeletal muscle, junctophilins (JPHs) 1 and 2 form the SR-PM junctions at which voltage-induced calcium release occurs. Previous work demonstrated that JPH2 is able to recapitulate voltage-induced calcium release when expressed in HEK293 cells together with CaV1.1, β1a, Stac3, and RYR1. However, it is unknown whether JPH1 and the more distantly related neuronal JPH3 and JPH4 might also function in this manner, a question of interest because different JPH isoforms diverge in their interactions with RYR1. Here, we show that, like JPH2, JPH1 and JPH3, coexpressed with CaV1.1, β1a, Stac3, and RYR1 in HEK293 cells, cause colocalization of CaV1.1 and RYR1 at ER-PM junctions. Furthermore, potassium depolarization elicited cytoplasmic calcium transients in cells in which WT CaV1.1 was replaced with the calcium impermeant mutant CaV1.1(N617D), indicating that JPH1, JPH2, and JPH3 can all support voltage-induced calcium release, despite sequence divergence and differences in interaction with RYR1. Conversely, JPH4-induced ER-PM junctions contain CaV1.1 but not RYR1, and cells expressing JPH4 are unable to produce depolarization-induced calcium transients. Thus, JPHs seem to act primarily to form ER-PM junctions and to recruit the necessary signaling proteins to these junctions but appear not to be directly involved in the functional interactions between these proteins.","PeriodicalId":173753,"journal":{"name":"The Journal of General Physiology","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2022-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/c2/e2/JGP_202113024.PMC9488633.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39866486","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: 2

A model for how Gβγ couples Gα to GPCR. Gβγ如何将Gα偶联到GPCR的模型。

IF 3.8

The Journal of General Physiology Pub Date : 2022-05-02 Epub Date: 2022-03-25 DOI: 10.1085/jgp.202112982

William E McIntire

引用次数: 4

Burmese pythons exhibit a transient adaptation to nutrient overload that prevents liver damage. 缅甸蟒蛇表现出对营养过剩的短暂适应，以防止肝脏受损。

IF 3.8

The Journal of General Physiology Pub Date : 2022-04-04 Epub Date: 2022-03-24 DOI: 10.1085/jgp.202113008

Jason A Magida, Yuxiao Tan, Christopher E Wall, Brooke C Harrison, Thomas G Marr, Angela K Peter, Cecilia A Riquelme, Leslie A Leinwand

{"title":"Burmese pythons exhibit a transient adaptation to nutrient overload that prevents liver damage.","authors":"Jason A Magida, Yuxiao Tan, Christopher E Wall, Brooke C Harrison, Thomas G Marr, Angela K Peter, Cecilia A Riquelme, Leslie A Leinwand","doi":"10.1085/jgp.202113008","DOIUrl":"https://doi.org/10.1085/jgp.202113008","url":null,"abstract":"As an opportunistic predator, the Burmese python (Python molurus bivittatus) consumes large and infrequent meals, fasting for up to a year. Upon consuming a large meal, the Burmese python exhibits extreme metabolic responses. To define the pathways that regulate these postprandial metabolic responses, we performed a comprehensive profile of plasma metabolites throughout the digestive process. Following ingestion of a meal equivalent to 25% of its body mass, plasma lipoproteins and metabolites, such as chylomicra and bile acids, reach levels observed only in mammalian models of extreme dyslipidemia. Here, we provide evidence for an adaptive response to postprandial nutrient overload by the python liver, a critical site of metabolic homeostasis. The python liver undergoes a substantial increase in mass through proliferative processes, exhibits hepatic steatosis, hyperlipidemia-induced insulin resistance indicated by PEPCK activation and pAKT deactivation, and de novo fatty acid synthesis via FASN activation. This postprandial state is completely reversible. We posit that Burmese pythons evade the permanent hepatic damage associated with these metabolic states in mammals using evolved protective measures to inactivate these pathways. These include a transient activation of hepatic nuclear receptors induced by fatty acids and bile acids, including PPAR and FXR, respectively. The stress-induced p38 MAPK pathway is also transiently activated during the early stages of digestion. Taken together, these data identify a reversible metabolic response to hyperlipidemia by the python liver, only achieved in mammals by pharmacologic intervention. The factors involved in these processes may be relevant to or leveraged for remediating human hepatic pathology.","PeriodicalId":173753,"journal":{"name":"The Journal of General Physiology","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2022-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/c7/ff/JGP_202113008.PMC8958269.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40318629","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: 2

The versatile regulation of K2P channels by polyanionic lipids of the phosphoinositide and fatty acid metabolism. 多阴离子脂质对磷酸肌肽和脂肪酸代谢的K2P通道的多功能调节。

IF 3.8

The Journal of General Physiology Pub Date : 2022-02-07 Epub Date: 2021-12-20 DOI: 10.1085/jgp.202112989

Elena B Riel, Björn C Jürs, Sönke Cordeiro, Marianne Musinszki, Marcus Schewe, Thomas Baukrowitz

{"title":"The versatile regulation of K2P channels by polyanionic lipids of the phosphoinositide and fatty acid metabolism.","authors":"Elena B Riel, Björn C Jürs, Sönke Cordeiro, Marianne Musinszki, Marcus Schewe, Thomas Baukrowitz","doi":"10.1085/jgp.202112989","DOIUrl":"https://doi.org/10.1085/jgp.202112989","url":null,"abstract":"Work over the past three decades has greatly advanced our understanding of the regulation of Kir K+ channels by polyanionic lipids of the phosphoinositide (e.g., PIP2) and fatty acid metabolism (e.g., oleoyl-CoA). However, comparatively little is known regarding the regulation of the K2P channel family by phosphoinositides and by long-chain fatty acid-CoA esters, such as oleoyl-CoA. We screened 12 mammalian K2P channels and report effects of polyanionic lipids on all tested channels. We observed activation of members of the TREK, TALK, and THIK subfamilies, with the strongest activation by PIP2 for TRAAK and the strongest activation by oleoyl-CoA for TALK-2. By contrast, we observed inhibition for members of the TASK and TRESK subfamilies. Our results reveal that TASK-2 channels have both activatory and inhibitory PIP2 sites with different affinities. Finally, we provided evidence that PIP2 inhibition of TASK-1 and TASK-3 channels is mediated by closure of the recently identified lower X-gate as critical mutations within the gate (i.e., L244A, R245A) prevent PIP2-induced inhibition. Our findings establish that K+ channels of the K2P family are highly sensitive to polyanionic lipids, extending our knowledge of the mechanisms of lipid regulation and implicating the metabolism of these lipids as possible effector pathways to regulate K2P channel activity.","PeriodicalId":173753,"journal":{"name":"The Journal of General Physiology","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2022-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/ff/06/JGP_202112989.PMC8693234.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39853941","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

Catecholamines are key modulators of ventricular repolarization patterns in the ball python (Python regius). 儿茶酚胺是球蟒(python regius)心室复极模式的关键调节剂。

IF 3.8

The Journal of General Physiology Pub Date : 2022-02-07 Epub Date: 2021-12-15 DOI: 10.1085/jgp.202012761

Bastiaan J D Boukens, William Joyce, Ditte Lind Kristensen, Ingeborg Hooijkaas, Aldo Jongejan, Tobias Wang, Bjarke Jensen

{"title":"Catecholamines are key modulators of ventricular repolarization patterns in the ball python (Python regius).","authors":"Bastiaan J D Boukens, William Joyce, Ditte Lind Kristensen, Ingeborg Hooijkaas, Aldo Jongejan, Tobias Wang, Bjarke Jensen","doi":"10.1085/jgp.202012761","DOIUrl":"https://doi.org/10.1085/jgp.202012761","url":null,"abstract":"Ectothermic vertebrates experience daily changes in body temperature, and anecdotal observations suggest these changes affect ventricular repolarization such that the T-wave in the ECG changes polarity. Mammals, in contrast, can maintain stable body temperatures, and their ventricular repolarization is strongly modulated by changes in heart rate and by sympathetic nervous system activity. The aim of this study was to assess the role of body temperature, heart rate, and circulating catecholamines on local repolarization gradients in the ectothermic ball python (Python regius). We recorded body-surface electrocardiograms and performed open-chest high-resolution epicardial mapping while increasing body temperature in five pythons, in all of which there was a change in T-wave polarity. However, the vector of repolarization differed between individuals, and only a subset of leads revealed T-wave polarity change. RNA sequencing revealed regional differences related to adrenergic signaling. In one denervated and Ringer's solution-perfused heart, heating and elevated heart rates did not induce change in T-wave polarity, whereas noradrenaline did. Accordingly, electrocardiograms in eight awake pythons receiving intra-arterial infusion of the β-adrenergic receptor agonists adrenaline and isoproterenol revealed T-wave inversion in most individuals. Conversely, blocking the β-adrenergic receptors using propranolol prevented T-wave change during heating. Our findings indicate that changes in ventricular repolarization in ball pythons are caused by increased tone of the sympathetic nervous system, not by changes in temperature. Therefore, ventricular repolarization in both pythons and mammals is modulated by evolutionary conserved mechanisms involving catecholaminergic stimulation.","PeriodicalId":173753,"journal":{"name":"The Journal of General Physiology","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2022-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/11/33/JGP_202012761.PMC8679508.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39728005","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: 2

Sarcomere length in the beating heart: Synchronicity is optional. 跳动心脏的肌节长度:同步性可选。

IF 3.8

The Journal of General Physiology Pub Date : 2022-02-07 Epub Date: 2022-01-10 DOI: 10.1085/jgp.202113022

Michiel Helmes, Bradley M Palmer

引用次数: 2