Channels (Austin, Tex.)最新文献_第5页

Association of respiratory failure with inhibition of NaV1.6 in the phrenic nerve. 膈神经中NaV1.6抑制与呼吸衰竭的关系。

Channels (Austin, Tex.) Pub Date : 2022-12-01 DOI: 10.1080/19336950.2022.2122309

Rebecca M Klein, Mark E Layton, Hillary Regan, Christopher P Regan, Yuxing Li, Tracey Filzen, Matt Cato, Michelle K Clements, Jixin Wang, Raul Sanoja, Thomas J Greshock, Anthony J Roecker, Joseph E Pero, Ron Kim, Christopher Burgey, Christopher T John, Ying-Hong Wang, Neetesh Bhandari, Arie Struyk, Richard L Kraus, Darrell A Henze, Andrea K Houghton

{"title":"Association of respiratory failure with inhibition of NaV1.6 in the phrenic nerve.","authors":"Rebecca M Klein, Mark E Layton, Hillary Regan, Christopher P Regan, Yuxing Li, Tracey Filzen, Matt Cato, Michelle K Clements, Jixin Wang, Raul Sanoja, Thomas J Greshock, Anthony J Roecker, Joseph E Pero, Ron Kim, Christopher Burgey, Christopher T John, Ying-Hong Wang, Neetesh Bhandari, Arie Struyk, Richard L Kraus, Darrell A Henze, Andrea K Houghton","doi":"10.1080/19336950.2022.2122309","DOIUrl":"https://doi.org/10.1080/19336950.2022.2122309","url":null,"abstract":"As part of a drug discovery effort to identify potent inhibitors of NaV1.7 for the treatment of pain, we observed that inhibitors produced unexpected cardiovascular and respiratory effects in vivo. Specifically, inhibitors administered to rodents produced changes in cardiovascular parameters and respiratory cessation. We sought to determine the mechanism of the in vivo adverse effects by studying the selectivity of the compounds on NaV1.5, NaV1.4, and NaV1.6 in in vitro and ex vivo assays. Inhibitors lacking sufficient NaV1.7 selectivity over NaV1.6 were associated with respiratory cessation after in vivo administration to rodents. Effects on respiratory rate in rats were consistent with effects in an ex vivo hemisected rat diaphragm model and in vitro NaV1.6 potency. Furthermore, direct blockade of the phrenic nerve signaling was observed at exposures known to cause respiratory cessation in rats. Collectively, these results support a significant role for NaV1.6 in phrenic nerve signaling and respiratory function.","PeriodicalId":72555,"journal":{"name":"Channels (Austin, Tex.)","volume":"16 1","pages":"230-243"},"PeriodicalIF":0.0,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9578445/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10686089","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

Small molecule targeting NaV1.7 via inhibition of the CRMP2-Ubc9 interaction reduces pain in chronic constriction injury (CCI) rats. 通过抑制CRMP2-Ubc9相互作用靶向NaV1.7的小分子可减轻慢性收缩损伤(CCI)大鼠的疼痛。

Channels (Austin, Tex.) Pub Date : 2022-12-01 DOI: 10.1080/19336950.2021.2023383

Jiahe Li, Harrison J Stratton, Sabina A Lorca, Peter M Grace, Rajesh Khanna

{"title":"Small molecule targeting NaV1.7 via inhibition of the CRMP2-Ubc9 interaction reduces pain in chronic constriction injury (CCI) rats.","authors":"Jiahe Li, Harrison J Stratton, Sabina A Lorca, Peter M Grace, Rajesh Khanna","doi":"10.1080/19336950.2021.2023383","DOIUrl":"https://doi.org/10.1080/19336950.2021.2023383","url":null,"abstract":"The voltage-gated sodium channel isoform NaV1.7 is a critical player in the transmission of nociceptive information. This channel has been heavily implicated in human genetic pain disorders and is a validated pain target. However, targeting this channel directly has failed, and an indirect approach - disruption of interactions with accessory protein partners - has emerged as a viable alternative strategy. We recently reported that a small-molecule inhibitor of CRMP2 SUMOylation, compound 194, selectively reduces NaV1.7 currents in DRG neurons across species from mouse to human. This compound also reversed mechanical allodynia in a spared nerve injury and chemotherapy-induced model of neuropathic pain. Here, we show that oral administration of 194 reverses mechanical allodynia in a chronic constriction injury (CCI) model of neuropathic pain. Furthermore, we show that orally administered 194 reverses the increased latency to cross an aversive barrier in a mechanical conflict-avoidance task following CCI. These two findings, in the context of our previous report, support the conclusion that 194 is a robust inhibitor of NaV1.7 function with the ultimate effect of profoundly ameliorating mechanical allodynia associated with nerve injury. The fact that this was observed using both traditional, evoked measures of pain behavior as well as the more recently developed operator-independent mechanical conflict-avoidance assay increases confidence in the efficacy of 194-induced anti-nociception.","PeriodicalId":72555,"journal":{"name":"Channels (Austin, Tex.)","volume":" ","pages":"1-8"},"PeriodicalIF":0.0,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8741281/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39873967","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: 7

Cardiogenic shock due to yew poisoning rescued by VA-ECMO: case report and literature review. VA-ECMO抢救红豆杉中毒心源性休克1例并文献复习。

Channels (Austin, Tex.) Pub Date : 2022-12-01 DOI: 10.1080/19336950.2022.2104886

Nikolaus Schreiber, Martin Manninger, Sascha Pätzold, Alexander C Reisinger, Stefan Hatzl, Gerald Hackl, Christoph Högenauer, Philipp Eller

引用次数: 3

Mechanism of carvedilol induced action potential and calcium alternans. 卡维地洛诱导动作电位和钙离子交换的机制。

Channels (Austin, Tex.) Pub Date : 2022-12-01 DOI: 10.1080/19336950.2022.2055521

Elizabeth Martinez-Hernandez, Giedrius Kanaporis, Lothar A Blatter

{"title":"Mechanism of carvedilol induced action potential and calcium alternans.","authors":"Elizabeth Martinez-Hernandez, Giedrius Kanaporis, Lothar A Blatter","doi":"10.1080/19336950.2022.2055521","DOIUrl":"https://doi.org/10.1080/19336950.2022.2055521","url":null,"abstract":"Carvedilol is a nonspecific β-blocker clinically used for the treatment of cardiovascular diseases but has also been shown to have profound effects on excitation-contraction coupling and Ca signaling at the cellular level. We investigate the mechanism by which carvedilol facilitates Ca transient (CaT) and action potential duration (APD) alternans in rabbit atrial myocytes. Carvedilol lowered the frequency threshold for pacing-induced CaT alternans and facilitated alternans in a concentration-dependent manner. Carvedilol prolonged the sarcoplasmic reticulum (SR) Ca release refractoriness by significantly increasing the time constant τ of recovery of SR Ca release; however, no changes in L-type calcium current recovery from inactivation or SR Ca load were found after carvedilol treatment. Carvedilol enhanced the degree of APD alternans nearly two-fold. Carvedilol slowed the APD restitution kinetics and steepened the APD restitution curve at the pacing frequency (2 Hz) where alternans were elicited. No effect on the CaT or APD alternans ratios was observed in experiments with a different β-blocker (metoprolol), excluding the possibility that the carvedilol effect on CaT and APD alternans was determined by its β-blocking properties. These data suggest that carvedilol contributes to the generation of CaT and APD alternans in atrial myocytes by modulating the restitution of CaT and APD.","PeriodicalId":72555,"journal":{"name":"Channels (Austin, Tex.)","volume":"16 1","pages":"97-112"},"PeriodicalIF":0.0,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9067505/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9316270","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: 4

Plant and fungi derived analgesic natural products targeting voltage-gated sodium and calcium channels. 靶向电压门控钠钙通道的植物和真菌衍生镇痛天然产物。

Channels (Austin, Tex.) Pub Date : 2022-12-01 DOI: 10.1080/19336950.2022.2103234

Aida Calderon-Rivera, Santiago Loya-Lopez, Kimberly Gomez, Rajesh Khanna

{"title":"Plant and fungi derived analgesic natural products targeting voltage-gated sodium and calcium channels.","authors":"Aida Calderon-Rivera, Santiago Loya-Lopez, Kimberly Gomez, Rajesh Khanna","doi":"10.1080/19336950.2022.2103234","DOIUrl":"https://doi.org/10.1080/19336950.2022.2103234","url":null,"abstract":"Voltage-gated sodium and calcium channels (VGSCs and VGCCs) play an important role in the modulation of physiologically relevant processes in excitable cells that range from action potential generation to neurotransmission. Once their expression and/or function is altered in disease, specific pharmacological approaches become necessary to mitigate the negative consequences of such dysregulation. Several classes of small molecules have been developed with demonstrated effectiveness on VGSCs and VGCCs; however, off-target effects have also been described, limiting their use and spurring efforts to find more specific and safer molecules to target these channels. There are a great number of plants and herbal preparations that have been empirically used for the treatment of diseases in which VGSCs and VGCCs are involved. Some of these natural products have progressed to clinical trials, while others are under investigation for their action mechanisms on signaling pathways, including channels. In this review, we synthesize information from ~30 compounds derived from natural sources like plants and fungi and delineate their effects on VGSCs and VGCCs in human disease, particularly pain. [Figure: see text].","PeriodicalId":72555,"journal":{"name":"Channels (Austin, Tex.)","volume":"16 1","pages":"198-215"},"PeriodicalIF":0.0,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9423853/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10631869","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: 1

Rab35 GTPase positively regulates endocytic recycling of cardiac K_ATP channels. Rab35 GTPase正调控心脏KATP通道的内吞循环。

Channels (Austin, Tex.) Pub Date : 2022-12-01 DOI: 10.1080/19336950.2022.2090667

Bo Yang, Jia-Lu Yao, Jian-Yi Huo, Yu-Long Feng, William A Coetzee, Guang-Yin Xu, Hua-Qian Yang

{"title":"Rab35 GTPase positively regulates endocytic recycling of cardiac KATP channels.","authors":"Bo Yang, Jia-Lu Yao, Jian-Yi Huo, Yu-Long Feng, William A Coetzee, Guang-Yin Xu, Hua-Qian Yang","doi":"10.1080/19336950.2022.2090667","DOIUrl":"https://doi.org/10.1080/19336950.2022.2090667","url":null,"abstract":"ATP-sensitive K+ (KATP) channel couples membrane excitability to intracellular energy metabolism. Maintaining KATP channel surface expression is key to normal insulin secretion, blood pressure and cardioprotection. However, the molecular mechanisms regulating KATP channel internalization and endocytic recycling, which directly affect the surface expression of KATP channels, are poorly understood. Here we used the cardiac KATP channel subtype, Kir6.2/SUR2A, and characterized Rab35 GTPase as a key regulator of KATP channel endocytic recycling. Electrophysiological recordings and surface biotinylation assays showed decreased KATP channel surface density with co-expression of a dominant negative Rab35 mutant (Rab35-DN), but not other recycling-related Rab GTPases, including Rab4, Rab11a and Rab11b. Immunofluorescence images revealed strong colocalization of Rab35-DN with recycling Kir6.2. Rab35-DN minimized the recycling rate of KATP channels. Rab35 also regulated KATP channel current amplitude in isolated adult cardiomyocytes by affecting its surface expression but not channel properties, which validated its physiologic relevance and the potential of pharmacologic target for treating the diseases with KATP channel trafficking defects.","PeriodicalId":72555,"journal":{"name":"Channels (Austin, Tex.)","volume":" ","pages":"137-147"},"PeriodicalIF":0.0,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9721419/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40401102","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

Exploring mutation specific beta blocker pharmacology of the pathogenic late sodium channel current from patient-specific pluripotent stem cell myocytes derived from long QT syndrome mutation carriers. 探索突变特异性β受体阻滞剂对来自长QT综合征突变携带者的患者特异性多能干细胞肌细胞致病性晚期钠通道电流的药理学作用。

Channels (Austin, Tex.) Pub Date : 2022-12-01 DOI: 10.1080/19336950.2022.2106025

Thomas W Comollo, Xinle Zou, Chuangeng Zhang, Divya Kesters, Thomas Hof, Kevin J Sampson, Robert S Kass

{"title":"Exploring mutation specific beta blocker pharmacology of the pathogenic late sodium channel current from patient-specific pluripotent stem cell myocytes derived from long QT syndrome mutation carriers.","authors":"Thomas W Comollo, Xinle Zou, Chuangeng Zhang, Divya Kesters, Thomas Hof, Kevin J Sampson, Robert S Kass","doi":"10.1080/19336950.2022.2106025","DOIUrl":"https://doi.org/10.1080/19336950.2022.2106025","url":null,"abstract":"The congenital long QT syndrome (LQTS), one of the most common cardiac channelopathies, is characterized by delayed ventricular repolarization underlying prolongation of the QT interval of the surface electrocardiogram. LQTS is caused by mutations in genes coding for cardiac ion channels or ion channel-associated proteins. The major therapeutic approach to LQTS management is beta blocker therapy which has been shown to be effective in treatment of LQTS variants caused by mutations in K+ channels. However, this approach has been questioned in the treatment of patients identified as LQTS variant 3(LQT3) patients who carry mutations in SCN5A, the gene coding for the principal cardiac Na+ channel. LQT3 mutations are gain of function mutations that disrupt spontaneous Na+ channel inactivation and promote persistent or late Na+ channel current (INaL) that delays repolarization and underlies QT prolongation. Clinical investigation of patients with the two most common LQT3 mutations, the ΔKPQ and the E1784K mutations, found beta blocker treatment a useful therapeutic approach for managing arrhythmias in this patient population. However, there is little experimental data that reveals the mechanisms underlying these antiarrhythmic actions. Here, we have investigated the effects of the beta blocker propranolol on INaL expressed by ΔKPQ and E1784K channels in induced pluripotent stem cells derived from patients carrying these mutations. Our results indicate that propranolol preferentially inhibits INaL expressed by these channels suggesting that the protective effects of propranolol in treating LQT3 patients is due in part to modulation of INaL.","PeriodicalId":72555,"journal":{"name":"Channels (Austin, Tex.)","volume":"16 1","pages":"173-184"},"PeriodicalIF":0.0,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9373745/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10637560","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: 1

Piezo1 activation facilitates ovarian cancer metastasis via Hippo/YAP signaling axis. Piezo1激活通过Hippo/YAP信号轴促进卵巢癌转移。

Channels (Austin, Tex.) Pub Date : 2022-12-01 DOI: 10.1080/19336950.2022.2099381

Yanjie Xiong, Liru Dong, Yun Bai, Hui Tang, Shuang Li, Dan Luo, Fang Liu, Jie Bai, Shikun Yang, Xudong Song

{"title":"Piezo1 activation facilitates ovarian cancer metastasis via Hippo/YAP signaling axis.","authors":"Yanjie Xiong, Liru Dong, Yun Bai, Hui Tang, Shuang Li, Dan Luo, Fang Liu, Jie Bai, Shikun Yang, Xudong Song","doi":"10.1080/19336950.2022.2099381","DOIUrl":"https://doi.org/10.1080/19336950.2022.2099381","url":null,"abstract":"Ovarian cancer (OC) is a highly malignant cancer with great metastatic potential. Here we aimed to investigate the role of Piezo1, a gene related to the mechanical environment of the tumor, in promoting the metastasis of OC. We performed Piezo1 knockdown in A-1847 cells using small hairpin RNAs, and the cells were inoculated subcutaneously in nude mice. Piezo1 knockdown decreased the tumor growth rate of OC tumor xenografts in mice and reduced cell migration in vitro. Metastasis in the lung was also attenuated after Piezo1 knockdown as revealed by HE staining of the lung tissues, which was concomitant with downregulation of E-Cadherin and vimentin and upregulation of N-Cadherin analyzed using western blot analysis, suggesting suppressed epithelial-to-mesenchymal transition. Migration of Piezo1-knockdown cells was also analyzed for their migratory capabilities using the scratch assay. We also analyzed the key proteins in the Hippo/YAP signaling pathway using western blot after treating A-1847 and 3AO cells with a Piezo1 inducer, Yoda1. Piezo1 inducer Yoda1 activated Hippo/YAP signal in OC cells. In conclusion, Piezo1 is overexpressed in OC tissues and contributes to OC tumor growth and metastasis. Suppression of Piezo1 is a potential therapeutic strategy for OC.","PeriodicalId":72555,"journal":{"name":"Channels (Austin, Tex.)","volume":" ","pages":"159-166"},"PeriodicalIF":0.0,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9367648/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40612286","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

Non-conducting functions of ion channels: The case of integrin-ion channel complexes. 离子通道的非导电功能:整合离子通道复合物的情况。

Channels (Austin, Tex.) Pub Date : 2022-12-01 DOI: 10.1080/19336950.2022.2108565

Elena Forzisi, Federico Sesti

{"title":"Non-conducting functions of ion channels: The case of integrin-ion channel complexes.","authors":"Elena Forzisi, Federico Sesti","doi":"10.1080/19336950.2022.2108565","DOIUrl":"https://doi.org/10.1080/19336950.2022.2108565","url":null,"abstract":"Started as an academic curiosity more than two decades ago, the idea that ion channels can regulate cellular processes in ways that do not depend on their conducting properties (non-ionic functions) gained traction and is now a flourishing area of research. Channels can regulate physiological processes including actin cytoskeletal remodeling, cell motility, excitation-contraction coupling, non-associative learning and embryogenesis, just to mention some, through non-ionic functions. When defective, non-ionic functions can give rise to channelopathies involved in cancer, neurodegenerative disease and brain trauma. Ion channels exert their non-ionic functions through a variety of mechanisms that range from physical coupling with other proteins, to possessing enzymatic activity, to assembling with signaling molecules. In this article, we take stock of the field and review recent findings. The concept that emerges, is that one of the most common ways through which channels acquire non-ionic attributes, is by assembling with integrins. These integrin-channel complexes exhibit broad genotypic and phenotypic heterogeneity and reveal a pleiotropic nature, as they appear to be capable of influencing both physiological and pathological processes.","PeriodicalId":72555,"journal":{"name":"Channels (Austin, Tex.)","volume":" ","pages":"185-197"},"PeriodicalIF":0.0,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9364710/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40691770","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: 5

A SWELL time to develop the molecular pharmacology of the volume-regulated anion channel (VRAC). 体积调节阴离子通道(VRAC)的分子药理学研究是一个非常好的时期。

Channels (Austin, Tex.) Pub Date : 2022-12-01 DOI: 10.1080/19336950.2022.2033511

Eric E Figueroa, Jerod S Denton

引用次数: 6