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https://www.readbyqxmd.com/read/28916724/a-novel-mechanism-for-ca-2-calmodulin-dependent-protein-kinase-ii-targeting-to-l-type-ca-2-channels-that-initiates-long-range-signaling-to-the-nucleus
#1
Xiaohan Wang, Christian R Marks, Tyler L Perfitt, Terunaga Nakagawa, Amy Lee, David A Jacobson, Roger J Colbran
Neuronal excitation can induce new mRNA transcription, a phenomenon called excitation-transcription (E-T) coupling. Among several pathways implicated in E-T coupling, activation of voltage-gated L-type Ca(2+) channels (LTCCs) in the plasma membrane can initiate a signaling pathway that ultimately increases nuclear CREB phosphorylation and, in most cases, expression of immediate early genes. Initiation of this long-range pathway has been shown to require recruitment of Ca(2+)-sensitive enzymes to a nanodomain in the immediate vicinity of the LTCC by an unknown mechanism...
September 15, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28912545/the-cacna1h-mutation-in-the-gaers-model-of-absence-epilepsy-enhances-t-type-ca-2-currents-by-altering-calnexin-dependent-trafficking-of-cav3-2-channels
#2
Juliane Proft, Yuriy Rzhepetskyy, Joanna Lazniewska, Fang-Xiong Zhang, Stuart M Cain, Terrance P Snutch, Gerald W Zamponi, Norbert Weiss
Low-voltage-activated T-type calcium channels are essential contributors to the functioning of thalamocortical neurons by supporting burst-firing mode of action potentials. Enhanced T-type calcium conductance has been reported in the Genetic Absence Epilepsy Rat from Strasbourg (GAERS) and proposed to be causally related to the overall development of absence seizure activity. Here, we show that calnexin, an endoplasmic reticulum integral membrane protein, interacts with the III-IV linker region of the Cav3...
September 14, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28899000/rhoa-rock-signalling-is-necessary-for-lateralization-and-differentiation-of-the-developing-sinoatrial-node
#3
Rebecca Vicente-Steijn, Tim P Kelder, Leon G Tertoolen, Lambertus J Wisse, Daniël A Pijnappels, Robert E Poelmann, Martin J Schalij, Marco C deRuiter, Adriana C Gittenberger-de Groot, Monique R M Jongbloed
Aims: RHOA-ROCK signalling regulates cell migration, proliferation, differentiation, and transcription. RHOA is expressed in the developing cardiac conduction system in chicken and mice. In early development, the entire sinus venosus myocardium, including both the transient left-sided and the definitive sinoatrial node (SAN), has pacemaker potential. Later, pacemaker potential is restricted to the right-sided SAN. Disruption of RHOA expression in adult mice causes arrhythmias including bradycardia and atrial fibrillation, the mechanism of which is unknown but presumed to affect the SAN...
August 1, 2017: Cardiovascular Research
https://www.readbyqxmd.com/read/28880874/discovery-and-mode-of-action-of-a-novel-analgesic-%C3%AE-toxin-from-the-african-spider-ceratogyrus-darlingi
#4
Silmara R Sousa, Joshua S Wingerd, Andreas Brust, Christopher Bladen, Lotten Ragnarsson, Volker Herzig, Jennifer R Deuis, Sebastien Dutertre, Irina Vetter, Gerald W Zamponi, Glenn F King, Paul F Alewood, Richard J Lewis
Spider venoms are rich sources of peptidic ion channel modulators with important therapeutical potential. We screened a panel of 60 spider venoms to find modulators of ion channels involved in pain transmission. We isolated, synthesized and pharmacologically characterized Cd1a, a novel peptide from the venom of the spider Ceratogyrus darlingi. Cd1a reversibly paralysed sheep blowflies (PD50 of 1318 pmol/g) and inhibited human Cav2.2 (IC50 2.6 μM) but not Cav1.3 or Cav3.1 (IC50 > 30 μM) in fluorimetric assays...
2017: PloS One
https://www.readbyqxmd.com/read/28837624/rare-variants-in-genes-encoding-the-cardiac-sodium-channel-and-associated-compounds-and-their-impact-on-outcome-of-catheter-ablation-of-atrial-fibrillation
#5
Daniela Husser, Laura Ueberham, Gerhard Hindricks, Petra Büttner, Christie Ingram, Peter Weeke, M Benjamin Shoemaker, Volker Adams, Arash Arya, Philipp Sommer, Dawood Darbar, Dan M Roden, Andreas Bollmann
AIM: Rare variants of genes encoding the cardiac sodium channel and associated compounds have been linked with atrial fibrillation (AF). Nevertheless, current expert consensus does not support genetic testing in AF, which is in part based on the fact that "there is no therapeutic impact derived from AF genetic test results". However, there are no studies available supporting this recommendation. Consequently, this study analyzed the impact of rare variants affecting the cardiac sodium channel on rhythm outcome of AF catheter ablation...
2017: PloS One
https://www.readbyqxmd.com/read/28829141/lycoplanine-a-a-c16n-lycopodium-alkaloid-with-a-6-9-5-tricyclic-skeleton-from-lycopodium-complanatum
#6
Zhi-Jun Zhang, Yin Nian, Qin-Feng Zhu, Xiao-Nian Li, Jia Su, Xing-De Wu, Jian Yang, Qin-Shi Zhao
Lycoplanine A (1), a Lycopodium alkaloid with a 6/9/5 tricyclic ring skeleton fused with the γ-lactone ring and featuring an unusual 1-oxa-6-azaspiro[4.4]nonane moiety and an unprecedented 3-azabicyclo[6.3.1]dodecane unit, was isolated from the club moss Lycopodium complanatum. The structure and absolute configuration of 1 were identified by a combination of NMR spectroscopic analysis and single-crystal X-ray diffraction. Biological studies showed that 1 is a potent Cav3.1 T-type calcium channel (TTCC) inhibitor with an IC50 value of 6...
August 22, 2017: Organic Letters
https://www.readbyqxmd.com/read/28807458/caveolin-3-deficiency-myopathy-associated-with-dyslipidemia-treatment-challenges-and-possible-pathophysiological-association
#7
Daiana Ibarretxe, Joan Pellejà, Nicolau Ortiz, Luis Masana
We report the case of a patient treated at the lipid clinic because of high cholesterol levels with consistently elevated creatine kinase concentrations that precluded statin treatment. Electromyography showed a rippling muscle disease pattern. A muscle biopsy confirmed caveolin 3 deficiency, and a missense mutation in the CAV3 gene was identified. The patient could be properly managed with ezetimibe and cholestyramine, which reduced the low-density lipoprotein cholesterol by 30%. He remains asymptomatic after 10 years of follow-up...
August 1, 2017: Journal of Clinical Lipidology
https://www.readbyqxmd.com/read/28800734/a-t-type-channel-calmodulin-complex-triggers-%C3%AE-camkii-activation
#8
Hadhimulya Asmara, Ileana Micu, Arsalan P Rizwan, Giriraj Sahu, Brett A Simms, Fang-Xiong Zhang, Jordan D T Engbers, Peter K Stys, Gerald W Zamponi, Ray W Turner
Calmodulin (CaM) is an important signaling molecule that regulates a vast array of cellular functions by activating second messengers involved in cell function and plasticity. Low voltage-activated calcium channels of the Cav3 family have the important role of mediating low threshold calcium influx, but were not believed to interact with CaM. We find a constitutive association between CaM and the Cav3.1 channel at rest that is lost through an activity-dependent and Cav3.1 calcium-dependent CaM dissociation...
August 11, 2017: Molecular Brain
https://www.readbyqxmd.com/read/28744923/the-role-of-t-type-calcium-channels-in-the-subiculum-to-burst-or-not-to-burst
#9
Srdjan M Joksimovic, Pierce Eggan, Yukitoshi Izumi, Sonja Lj Joksimovic, Vesna Tesic, Robert M Dietz, James E Orfila, Michael R DiGruccio, Paco S Herson, Vesna Jevtovic-Todorovic, Charles F Zorumski, Slobodan M Todorovic
KEY POINTS: Pharmacological, molecular and genetic data indicate a prominent role of low-voltage-activated T-type calcium channels (T-channels) in the firing activity of both pyramidal and inhibitory interneurons in the subiculum. Pharmacological inhibition of T-channels switched burst firing with lower depolarizing stimuli to regular spiking, and fully abolished hyperpolarization-induced burst firing. Our molecular studies showed that CaV 3.1 is the most abundantly expressed isoform of T-channels in the rat subiculum...
July 26, 2017: Journal of Physiology
https://www.readbyqxmd.com/read/28742985/gabab-receptors-suppress-burst-firing-in-reticular-thalamic-neurons
#10
Stuart M Cain, Esperanza Garcia, Zeina Waheed, Karen L Jones, Trevor J Bushell, Terrance P Snutch
Burst-firing in thalamic neurons is known to play a key role in mediating thalamocortical (TC) oscillations that are associated with non-REM sleep and some types of epileptic seizure. Within the TC system the primary output of GABAergic neurons in the reticular thalamic nucleus (RTN) is thought to induce the de-inactivation of T-type calcium channels in thalamic relay (TR) neurons, promoting burst-firing drive to the cortex and the propagation of TC network activity. However, RTN neurons also project back onto other neurons within the RTN...
July 25, 2017: Channels
https://www.readbyqxmd.com/read/28741432/-express-identification-of-interleukin-1-beta-as-a-key-mediator-in-the-upregulation-of-cav3-2-usp5-interactions-in-the-pain-pathway
#11
Patrick L Stemkowski, Agustin Garcia-Caballero, Vinicius M Gadotti, Said M'Dahoma, Lina Chen, Ivana A Souza, Gerald W Zamponi
No abstract text is available yet for this article.
January 2017: Molecular Pain
https://www.readbyqxmd.com/read/28720332/synthesis-and-biological-evaluation-of-fluoro-substituted-3-4-dihydroquinazoline-derivatives-for-cytotoxic-and-analgesic-effects
#12
Jin Han Kim, Hui Rak Jeong, Da Woon Jung, Hong Bin Yoon, Sun Young Kim, Hyoung Ja Kim, Kyung-Tae Lee, Vinicius M Gadotti, Junting Huang, Fang-Xiong Zhang, Gerald W Zamponi, Jae Yeol Lee
As a bioisosteric strategy to overcome the poor metabolic stability of lead compound KYS05090S, a series of new fluoro-substituted 3,4-dihydroquinazoline derivatives was prepared and evaluated for T-type calcium channel (Cav3.2) block, cytotoxic effects and liver microsomal stability. Among them, compound 8h (KCP10068F) containing 4-fluorobenzyl amide and 4-cyclohexylphenyl ring potently blocked Cav3.2 currents (>90% inhibition) at 10μM concentration and exhibited cytotoxic effect (IC50=5.9μM) in A549 non-small cell lung cancer cells that was comparable to KYS05090S...
July 8, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28701796/camk-ii-%C3%AE-down-regulation-protects-dorsal-root-ganglion-neurons-from-ropivacaine-hydrochloride-neurotoxicity
#13
Xian-Jie Wen, Xiao-Hong Li, Heng Li, Hua Liang, Chen-Xiang Yang, Han-Bing Wang
T-type calcium channels are intimately involved in the local anesthetics neurotoxicity. Does CaMKIIγ regulate T-type calcium currents in local anesthetics neurotoxicity? This study generated pAd-CaMKIIγ and pAd-shRNA adenovirus vectors to up- and down-regulate CaMKIIγ mRNA expression in dorsal root ganglion neurons (DRG). Normal DRG (Normal group), empty vector DRG (Empty vector group), pAd-CaMKIIγ DRG (pAd-CaMKIIγ group) and pAd-shRNA DRG (pAd-shRNA group) were treated or untreated with 3 mM ropivacaine hydrochloride for 4 h...
July 12, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28696213/ca-2-regulation-of-cav3-3-t-type-ca-2-channel-is-mediated-by-calmodulin
#14
Narae Lee, Sua Jeong, Kang-Chang Kim, Jin-Ah Kim, Jin-Yong Park, Ho-Won Kang, Edward Perez-Reyes, Jung-Ha Lee
Calcium-dependent inactivation of high voltage-activated Ca(2+) channels plays a crucial role in limiting rises in intracellular calcium (Ca(2+)i). A key mediator of these effects is calmodulin, which has been found to bind the C-terminus of the pore-forming α subunit. In contrast, little is known about how Ca(2+)i can regulate low voltage-activated T-type Ca(2+) channels. Using whole cell patch clamp, we examined the biophysical properties of Ca(2+) current through the three T-type Ca(2+) channel isoforms, Cav3...
September 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28687333/predicting-novel-genes-and-pathways-associated-with-osteosarcoma-by-using-bioinformatics-analysis
#15
Bo Dong, Guozhu Wang, Jie Yao, Puwei Yuan, Wulin Kang, Liqiang Zhi, Xijing He
This aim of this study was to explore novel biomarkers related to osteosarcoma. The mRNA expression profile GSE41293 dataset was downloaded from the Gene Expression Omnibus (GEO) database, which included seven osteosarcoma and six control samples. After preprocessing, the FASTQ format reads of 13 samples were mapped to the reference sequences to screen for unique mapping reads. Differentially expressed genes (DEGs) were selected, which were then used for pathway and protein-protein interaction (PPI) network analyses...
July 4, 2017: Gene
https://www.readbyqxmd.com/read/28662076/landscape-and-variation-of-novel-retroduplications-in-26-human-populations
#16
Yan Zhang, Shantao Li, Alexej Abyzov, Mark B Gerstein
Retroduplications come from reverse transcription of mRNAs and their insertion back into the genome. Here, we performed comprehensive discovery and analysis of retroduplications in a large cohort of 2,535 individuals from 26 human populations, as part of 1000 Genomes Phase 3. We developed an integrated approach to discover novel retroduplications combining high-coverage exome and low-coverage whole-genome sequencing data, utilizing information from both exon-exon junctions and discordant paired-end reads. We found 503 parent genes having novel retroduplications absent from the reference genome...
June 2017: PLoS Computational Biology
https://www.readbyqxmd.com/read/28658605/sociability-impairments-in-genetic-absence-epilepsy-rats-from-strasbourg-reversal-by-the-t-type-calcium-channel-antagonist-z944
#17
Mark T Henbid, Wendie N Marks, Madeline J Collins, Stuart M Cain, Terrance P Snutch, John G Howland
Childhood absence epilepsy (CAE) is associated with interictal co-morbid symptoms including abnormalities in social behaviour. Genetic Absence Epilepsy Rats from Strasbourg (GAERS) is a model of CAE that exhibits physiological and behavioural alterations characteristic of the human disorder. However, it is unknown if GAERS display the social deficits often observed in CAE. Sociability in rodents is thought to be mediated by neural circuits densely populated with T-type calcium channels and GAERS contain a missense mutation in the Cav3...
October 2017: Experimental Neurology
https://www.readbyqxmd.com/read/28655554/t-type-ca-2-channels-elicit-pro-proliferative-and-anti-apoptotic-responses-through-impaired-pp2a-akt1-signaling-in-pasmcs-from-patients-with-pulmonary-arterial-hypertension
#18
Safietou Sankhe, Sevasti Manousakidi, Fabrice Antigny, Jennifer Arthur Ataam, Sana Bentebbal, Yann Ruchon, Florence Lecerf, Jessica Sabourin, Laura Price, Elie Fadel, Peter Dorfmüller, Saadia Eddahibi, Marc Humbert, Frédéric Perros, Véronique Capuano
Idiopathic pulmonary arterial hypertension (iPAH) is characterized by obstructive hyperproliferation and apoptosis resistance of distal pulmonary artery smooth muscle cells (PASMCs). T-type Ca(2+) channel blockers have been shown to reduce experimental pulmonary hypertension, although the impact of T-type channel inhibition remains unexplored in PASMCs from iPAH patients. Here we show that T-type channels Cav3.1 and Cav3.2 are present in the lung and PASMCs from iPAH patients and control subjects. The blockade of T-type channels by the specific blocker, TTA-A2, prevents cell cycle progression and PASMCs growth...
June 24, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28648824/sheath-cell-invasion-and-trans-differentiation-repair-mechanical-damage-caused-by-loss-of-caveolae-in-the-zebrafish-notochord
#19
Jamie Garcia, Jennifer Bagwell, Brian Njaine, James Norman, Daniel S Levic, Susan Wopat, Sara E Miller, Xiaojing Liu, Jason W Locasale, Didier Y R Stainier, Michel Bagnat
The notochord, a conserved axial structure required for embryonic axis elongation and spine development, consists of giant vacuolated cells surrounded by an epithelial sheath [1-3]. During morphogenesis, vacuolated cells maintain their structural integrity despite being under constant mechanical stress [4]. We hypothesized that the high density of caveolae present in vacuolated cells [5, 6] could buffer mechanical tension. Caveolae are 50- to 80-nm membrane invaginations lined by cage-like polygonal structures [7, 8] formed by caveolin 1 (Cav1) or Cav3 and one of the cavin proteins [6, 9-11]...
July 10, 2017: Current Biology: CB
https://www.readbyqxmd.com/read/28639215/regulation-of-t-type-ca-2-channel-expression-by-herpes-simplex-virus-1-infection-in-sensory-like-nd7-cells
#20
Qiaojuan Zhang, Shao-Chung Hsia, Miguel Martin-Caraballo
Infection of sensory neurons by herpes simplex virus (HSV)-1 disrupts electrical excitability, altering pain sensory transmission. Because of their low threshold for activation, functional expression of T-type Ca(2+) channels regulates various cell functions, including neuronal excitability and neuronal communication. In this study, we have tested the effect of HSV-1 infection on the functional expression of T-type Ca(2+) channels in differentiated ND7-23 sensory-like neurons. Voltage-gated Ca(2+) currents were measured using whole cell patch clamp recordings in differentiated ND7-23 neurons under various culture conditions...
June 21, 2017: Journal of Neurovirology
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