Channels (Austin, Tex.)最新文献_第4页

Characterization of two pathological gating-charge substitutions in Cav1.4 L-type calcium channels. Cav1.4 l型钙通道中两种病理性门控电荷取代的表征。

Channels (Austin, Tex.) Pub Date : 2023-12-01 DOI: 10.1080/19336950.2023.2192360

Thomas Heigl, Michael A Netzer, Lucia Zanetti, Matthias Ganglberger, Monica L Fernández-Quintero, Alexandra Koschak

{"title":"Characterization of two pathological gating-charge substitutions in Cav1.4 L-type calcium channels.","authors":"Thomas Heigl, Michael A Netzer, Lucia Zanetti, Matthias Ganglberger, Monica L Fernández-Quintero, Alexandra Koschak","doi":"10.1080/19336950.2023.2192360","DOIUrl":"10.1080/19336950.2023.2192360","url":null,"abstract":"Cav1.4 L-type calcium channels are predominantly expressed at the photoreceptor terminals and in bipolar cells, mediating neurotransmitter release. Mutations in its gene, CACNA1F, can cause congenital stationary night-blindness type 2 (CSNB2). Due to phenotypic variability in CSNB2, characterization of pathological variants is necessary to better determine pathological mechanism at the site of action. A set of known mutations affects conserved gating charges in the S4 voltage sensor, two of which have been found in male CSNB2 patients. Here, we describe two disease-causing Cav1.4 mutations with gating charge neutralization, exchanging an arginine 964 with glycine (RG) or arginine 1288 with leucine (RL). In both, charge neutralization was associated with a reduction channel expression also reflected in smaller ON gating currents. In RL channels, the strong decrease in whole-cell current densities might additionally be explained by a reduction of single-channel currents. We further identified alterations in their biophysical properties, such as a hyperpolarizing shift of the activation threshold and an increase in slope factor of activation and inactivation. Molecular dynamic simulations in RL substituted channels indicated water wires in both, resting and active, channel states, suggesting the development of omega (ω)currents as a new pathological mechanism in CSNB2. This sum of the respective channel property alterations might add to the differential symptoms in patients beside other factors, such as genomic and environmental deviations.","PeriodicalId":72555,"journal":{"name":"Channels (Austin, Tex.)","volume":"17 1","pages":"2192360"},"PeriodicalIF":0.0,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10038055/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9539042","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

Effect of truncation on TRPM7 channel activity. 截断对TRPM7通道活性的影响。

Channels (Austin, Tex.) Pub Date : 2023-12-01 DOI: 10.1080/19336950.2023.2200874

Zhuqing Xie, Nashat Abumaria

{"title":"Effect of truncation on TRPM7 channel activity.","authors":"Zhuqing Xie, Nashat Abumaria","doi":"10.1080/19336950.2023.2200874","DOIUrl":"10.1080/19336950.2023.2200874","url":null,"abstract":"Transient receptor potential melastatin-like 7 (TRPM7) is a key player in various physiological and pathological processes. TRPM7 channel activity is regulated by different factors. The effects of cleavage of different domains on channel activity remain unknown. Here, we constructed several TRPM7 clones and explored the effects of truncating the mouse TRPM7 at different locations on the ion channel activity in two cell lines. We compared the clones' activity with the full-length TRPM7 and the native TRPM7 in transfected and untransfected cells. We also expressed fluorescently tagged truncated clones to examine their protein stability and membrane targeting. We found that truncating the kinase domain induced reduction in TRPM7 channel activity. Further truncations beyond the kinase (serine/threonine rich domain and/or coiled-coil domain) did not result in further reductions in channel activity. Two truncated clones lacking the TRP domain or the melastatin homology domain had a completely nonfunctional channel apparently due to disruption of protein stability. We identified the shortest structure of TRPM7 with measurable channel activity. We found that the truncated TRPM7 containing only S5 and S6 domains retained some channel activity. Adding the TRP domain to the S5-S6 resulted in a significant increase in channel activity. Finally, our analysis showed that TRPM7 outward currents are more sensitive to truncations than inward currents. Our data provide insights on the effects of truncating TRPM7 at different locations on the channel functions, highlighting the importance of different domains in impacting channel activity, protein stability, and/or membrane targeting.","PeriodicalId":72555,"journal":{"name":"Channels (Austin, Tex.)","volume":"17 1","pages":"2200874"},"PeriodicalIF":0.0,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10761173/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9577031","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

Overlap in synaptic neurological condition susceptibility pathways and the neural pannexin 1 interactome revealed by bioinformatics analyses. 生物信息学分析揭示了突触神经条件易感性途径和神经血管紧张素1相互作用组的重叠。

Channels (Austin, Tex.) Pub Date : 2023-12-01 Epub Date: 2023-10-08 DOI: 10.1080/19336950.2023.2253102

Simona D Frederiksen, Leigh E Wicki-Stordeur, Leigh Anne Swayne

{"title":"Overlap in synaptic neurological condition susceptibility pathways and the neural pannexin 1 interactome revealed by bioinformatics analyses.","authors":"Simona D Frederiksen, Leigh E Wicki-Stordeur, Leigh Anne Swayne","doi":"10.1080/19336950.2023.2253102","DOIUrl":"10.1080/19336950.2023.2253102","url":null,"abstract":"Many neurological conditions exhibit synaptic impairments, suggesting mechanistic convergence. Additionally, the pannexin 1 (PANX1) channel and signaling scaffold is linked to several of these neurological conditions and is an emerging regulator of synaptic development and plasticity; however, its synaptic pathogenic contributions are relatively unexplored. To this end, we explored connections between synaptic neurodevelopmental disorder and neurodegenerative disease susceptibility genes discovered by genome-wide association studies (GWASs), and the neural PANX1 interactome (483 proteins) identified from mouse Neuro2a (N2a) cells. To identify shared susceptibility genes, we compared synaptic suggestive GWAS candidate genes amongst autism spectrum disorders, schizophrenia, Parkinson's disease, and Alzheimer's disease. To further probe PANX1 signaling pathways at the synapse, we used bioinformatics tools to identify PANX1 interactome signaling pathways and protein-protein interaction clusters. To shed light on synaptic disease mechanisms potentially linking PANX1 and these four neurological conditions, we performed additional cross-analyses between gene ontologies enriched for the PANX1 synaptic and disease-susceptibility gene sets. Finally, to explore the regional specificity of synaptic PANX1-neurological condition connections, we identified brain region-specific elevations of synaptic PANX1 interactome and GWAS candidate gene set transcripts. Our results confirm considerable overlap in risk genes for autism spectrum disorders and schizophrenia and identify potential commonalities in genetic susceptibility for neurodevelopmental disorders and neurodegenerative diseases. Our findings also pinpointed novel putative PANX1 links to synaptic disease-associated pathways, such as regulation of vesicular trafficking and proteostasis, warranting further validation.","PeriodicalId":72555,"journal":{"name":"Channels (Austin, Tex.)","volume":"17 1","pages":"2253102"},"PeriodicalIF":0.0,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10563626/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41157876","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

Molecular pharmacology of the onco-TRP channel TRPV6. 肿瘤TRP通道TRPV6的分子药理学。

Channels (Austin, Tex.) Pub Date : 2023-12-01 Epub Date: 2023-10-15 DOI: 10.1080/19336950.2023.2266669

Arthur Neuberger, Alexander I Sobolevsky

引用次数: 0

L-type calcium channels and neuropsychiatric diseases: Insights into genetic risk variant-associated genomic regulation and impact on brain development. l型钙通道与神经精神疾病:遗传风险变异相关的基因组调控及其对大脑发育的影响

Channels (Austin, Tex.) Pub Date : 2023-12-01 DOI: 10.1080/19336950.2023.2176984

Madelyn R Baker, Andrew S Lee, Anjali M Rajadhyaksha

{"title":"L-type calcium channels and neuropsychiatric diseases: Insights into genetic risk variant-associated genomic regulation and impact on brain development.","authors":"Madelyn R Baker, Andrew S Lee, Anjali M Rajadhyaksha","doi":"10.1080/19336950.2023.2176984","DOIUrl":"10.1080/19336950.2023.2176984","url":null,"abstract":"Recent human genetic studies have linked a variety of genetic variants in the CACNA1C and CACNA1D genes to neuropsychiatric and neurodevelopmental disorders. This is not surprising given the work from multiple laboratories using cell and animal models that have established that Cav1.2 and Cav1.3 L-type calcium channels (LTCCs), encoded by CACNA1C and CACNA1D, respectively, play a key role in various neuronal processes that are essential for normal brain development, connectivity, and experience-dependent plasticity. Of the multiple genetic aberrations reported, genome-wide association studies (GWASs) have identified multiple single nucleotide polymorphisms (SNPs) in CACNA1C and CACNA1D that are present within introns, in accordance with the growing body of literature establishing that large numbers of SNPs associated with complex diseases, including neuropsychiatric disorders, are present within non-coding regions. How these intronic SNPs affect gene expression has remained a question. Here, we review recent studies that are beginning to shed light on how neuropsychiatric-linked non-coding genetic variants can impact gene expression via regulation at the genomic and chromatin levels. We additionally review recent studies that are uncovering how altered calcium signaling through LTCCs impact some of the neuronal developmental processes, such as neurogenesis, neuron migration, and neuron differentiation. Together, the described changes in genomic regulation and disruptions in neurodevelopment provide possible mechanisms by which genetic variants of LTCC genes contribute to neuropsychiatric and neurodevelopmental disorders.","PeriodicalId":72555,"journal":{"name":"Channels (Austin, Tex.)","volume":"17 1","pages":"2176984"},"PeriodicalIF":0.0,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9980663/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9598433","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

A systemic analysis of monocarboxylate transporters in ovarian cancer and possible therapeutic interventions. 卵巢癌症中单羧酸转运蛋白的系统分析及可能的治疗干预措施。

Channels (Austin, Tex.) Pub Date : 2023-12-01 Epub Date: 2023-11-07 DOI: 10.1080/19336950.2023.2273008

Priti Chatterjee, Debaleena Bhowmik, Sib Sankar Roy

{"title":"A systemic analysis of monocarboxylate transporters in ovarian cancer and possible therapeutic interventions.","authors":"Priti Chatterjee, Debaleena Bhowmik, Sib Sankar Roy","doi":"10.1080/19336950.2023.2273008","DOIUrl":"10.1080/19336950.2023.2273008","url":null,"abstract":"Monocarboxylate transporters (MCTs) play an immense role in metabolically active solid tumors by regulating concentration-dependent transport of different important monocarboxylates including pyruvate and lactate and are encoded by the SLC16A family of genes. Given the vast array of functions, these transporters play in oncogenesis, our objective was to look into the association of MCT1 (SLC16A1), MCT2 (SLC16A7), MCT3 (SLC16A8), and MCT4 (SLC16A3) with Epithelial ovarian cancer (EOC) pathophysiology by exploiting various publicly available databases and web resources. Few of the in silico findings were confirmed via in vitro experiments in EOC cell lines, SKOV3 and OAW-42. MCT1 and MCT4 were found to be upregulated at the mRNA level in OC tissues compared to normal. However, only higher level of MCT4 mRNA was found to be associated with poor patient survival. MCT4 was positively correlated with gene families responsible for invasion, migration, and immune modification, proving it to be one of the most important MCTs for therapeutic intervention. We compared the effects of MCT1/2 blocker SR13800 and a broad-spectrum MCT blocker α-Cyano Hydroxy Cinnamic Acid (α-CHCA) and discovered that α-CHCA has a greater effect on diminishing the invasive behavior of the cancer cells than MCT1/2 blocker SR13800. From our study, MCT4 has emerged as a prospective marker for predicting poor patient outcomes and a potential therapeutic target.","PeriodicalId":72555,"journal":{"name":"Channels (Austin, Tex.)","volume":"17 1","pages":"2273008"},"PeriodicalIF":0.0,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10631444/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71489617","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

Advances in Ca_V1.1 gating: New insights into permeation and voltage-sensing mechanisms. CaV1.1门控的新进展:渗透和电压传感机制的新见解。

Channels (Austin, Tex.) Pub Date : 2023-12-01 DOI: 10.1080/19336950.2023.2167569

Hugo Bibollet, Audra Kramer, Roger A Bannister, Erick O Hernández-Ochoa

引用次数: 0

Voltage gated sodium and calcium channels: Discovery, structure, function, and Pharmacology. 电压门控钠钙通道:发现、结构、功能和药理学。

Channels (Austin, Tex.) Pub Date : 2023-12-01 Epub Date: 2023-11-20 DOI: 10.1080/19336950.2023.2281714

William A Catterall

{"title":"Voltage gated sodium and calcium channels: Discovery, structure, function, and Pharmacology.","authors":"William A Catterall","doi":"10.1080/19336950.2023.2281714","DOIUrl":"10.1080/19336950.2023.2281714","url":null,"abstract":"Voltage-gated sodium channels initiate action potentials in nerve and muscle, and voltage-gated calcium channels couple depolarization of the plasma membrane to intracellular events such as secretion, contraction, synaptic transmission, and gene expression. In this Review and Perspective article, I summarize early work that led to identification, purification, functional reconstitution, and determination of the amino acid sequence of the protein subunits of sodium and calcium channels and showed that their pore-forming subunits are closely related. Decades of study by antibody mapping, site-directed mutagenesis, and electrophysiological recording led to detailed two-dimensional structure-function maps of the amino acid residues involved in voltage-dependent activation and inactivation, ion permeation and selectivity, and pharmacological modulation. Most recently, high-resolution three-dimensional structure determination by X-ray crystallography and cryogenic electron microscopy has revealed the structural basis for sodium and calcium channel function and pharmacological modulation at the atomic level. These studies now define the chemical basis for electrical signaling and provide templates for future development of new therapeutic agents for a range of neurological and cardiovascular diseases.","PeriodicalId":72555,"journal":{"name":"Channels (Austin, Tex.)","volume":"17 1","pages":"2281714"},"PeriodicalIF":0.0,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10761118/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138178172","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

Structural basis of properties, mechanisms, and channelopathy of cyclic nucleotide-gated channels. 环状核苷酸门控通道的性质、机制和通道病的结构基础。

Channels (Austin, Tex.) Pub Date : 2023-12-01 Epub Date: 2023-10-31 DOI: 10.1080/19336950.2023.2273165

Zhengshan Hu, Jian Yang

引用次数: 0

Cycling matters: Sex hormone regulation of vascular potassium channels. 循环问题:血管钾通道的性激素调节。

Channels (Austin, Tex.) Pub Date : 2023-12-01 DOI: 10.1080/19336950.2023.2217637

Samuel N Baldwin, Thomas A Jepps, Iain A Greenwood

{"title":"Cycling matters: Sex hormone regulation of vascular potassium channels.","authors":"Samuel N Baldwin, Thomas A Jepps, Iain A Greenwood","doi":"10.1080/19336950.2023.2217637","DOIUrl":"10.1080/19336950.2023.2217637","url":null,"abstract":"Sex hormones and the reproductive cycle (estrus in rodents and menstrual in humans) have a known impact on arterial function. In spite of this, sex hormones and the estrus/menstrual cycle are often neglected experimental factors in vascular basic preclinical scientific research. Recent research by our own laboratory indicates that cyclical changes in serum concentrations of sex -hormones across the rat estrus cycle, primary estradiol, have significant consequences for the subcellular trafficking and function of KV. Vascular potassium channels, including KV, are essential components of vascular reactivity. Our study represents a small part of a growing field of literature aimed at determining the role of sex hormones in regulating arterial ion channel function. This review covers key findings describing the current understanding of sex hormone regulation of vascular potassium channels, with a focus on KV channels. Further, we highlight areas of research where the estrus cycle should be considered in future studies to determine the consequences of physiological oscillations in concentrations of sex hormones on vascular potassium channel function.","PeriodicalId":72555,"journal":{"name":"Channels (Austin, Tex.)","volume":"17 1","pages":"2217637"},"PeriodicalIF":0.0,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10228406/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9581141","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