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https://www.readbyqxmd.com/read/28608534/recent-advances-in-the-development-of-t-type-calcium-channel-blockers-for-pain-intervention
#1
REVIEW
Terrance P Snutch, Gerald W Zamponi
Cav3.2 T-type calcium channels are important regulators of pain signals in afferent pain pathway, and their activities are dysregulated during various chronic pain states. Therefore it stands to reason that inhibiting T-type calcium channels in dorsal root ganglion neurons and in the spinal dorsal horn can be targeted for pain relief. This is supported by early pharmacological studies with T-type channel blockers such as ethosuximide, and by analgesic effects of siRNA depletion of Cav3.2 channels. In the past five years, considerable effort has been applied towards identifying novel classes of T-type calcium channel blockers...
June 13, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28603637/t-type-voltage-gated-ca-2-channels-do-not-contribute-to-the-negative-feedback-regulation-of-myogenic-tone-in-murine-superior-epigastric-arteries
#2
Brendan Mullan, Jessica Pettis, William F Jackson
T-type voltage-gated Ca(2+) channels (CaV3.2 VGCC) have been hypothesized to control spontaneous transient outward currents (STOCs) through large-conductance Ca(2+)-activated K(+) channels (BKCa), and contribute to the negative-feedback regulation of myogenic tone. We tested this hypothesis in superior epigastric arteries (SEAs) isolated from male C57BL/6 mice. SEAs were isolated and enzymatically dissociated to obtain single smooth muscle cells (SMCs) for whole-cell recording of paxilline-sensitive (PAX, 1 μmol/L) STOCs at -30 mV, or cannulated and studied by pressure myography (80 cm H2O, 37°C)...
June 2017: Pharmacology Research & Perspectives
https://www.readbyqxmd.com/read/28600496/dysregulation-of-nuclear-receptor-coup-tfii-impairs-skeletal-muscle-development
#3
Hui-Ju Lee, Chung-Yang Kao, Shih-Chieh Lin, Mafei Xu, Xin Xie, Sophia Y Tsai, Ming-Jer Tsai
Chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII) has been shown to inhibit myogenesis and skeletal muscle metabolism in vitro. However, its precise role and in vivo function in muscle development has yet to be clearly defined. COUP-TFII protein expression level is high in undifferentiated progenitors and gradually declines during differentiation, raising an important question of whether downregulation of COUP-TFII expression is required for proper muscle cell differentiation. In this study, we generated a mouse model ectopically expressing COUP-TFII in myogenic precursors to maintain COUP-TFII activity during myogenesis and found that elevated COUP-TFII activity resulted in inefficient skeletal muscle development...
June 9, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28556246/cacna1g-is-a-genetic-modifier-of-epilepsy-in-a-mouse-model-of-dravet-syndrome
#4
Jeffrey D Calhoun, Nicole A Hawkins, Nicole J Zachwieja, Jennifer A Kearney
Dravet syndrome, an early onset epileptic encephalopathy, is most often caused by de novo mutation of the neuronal voltage-gated sodium channel gene SCN1A. Mouse models with deletion of Scn1a recapitulate Dravet syndrome phenotypes, including spontaneous generalized tonic-clonic seizures, susceptibility to seizures induced by elevated body temperature, and elevated risk of sudden unexpected death in epilepsy. Importantly, the epilepsy phenotype of Dravet mouse models is highly strain-dependent, suggesting a strong influence of genetic modifiers...
May 28, 2017: Epilepsia
https://www.readbyqxmd.com/read/28542204/similar-regulatory-mechanisms-of-caveolins-and-cavins-by-myocardin-family-coactivators-in-arterial-and-bladder-smooth-muscle
#5
Baoyi Zhu, Catarina Rippe, Tran Thi Hien, Jianwen Zeng, Sebastian Albinsson, Karin G Stenkula, Bengt Uvelius, Karl Swärd
Caveolae are membrane invaginations present at high densities in muscle and fat. Recent work has demonstrated that myocardin family coactivators (MYOCD, MKL1), which are important for contractile differentiation and cell motility, increase caveolin (CAV1, CAV2, CAV3) and cavin (CAVIN1, CAVIN2, CAVIN3) transcription, but several aspects of this control mechanism remain to be investigated. Here, using promoter reporter assays we found that both MKL1/MRTF-A and MKL2/MRTF-B control caveolins and cavins via their proximal promoter sequences...
2017: PloS One
https://www.readbyqxmd.com/read/28522735/d3-receptors-regulate-excitability-in-a-unique-class-of-prefrontal-pyramidal-cells
#6
Rebecca L Clarkson, Alayna T Liptak, Steven M Gee, Vikaas S Sohal, Kevin J Bender
The D3 dopamine receptor, a member of the Gi-coupled D2 family of dopamine receptors, is expressed throughout limbic circuits affected in neuropsychiatric disorders, including prefrontal cortex (PFC). These receptors are important for prefrontal executive function because pharmacological and genetic manipulations that affect prefrontal D3 receptors alter anxiety, social interaction, and reversal learning. However, the mechanisms by which D3 receptors regulate prefrontal circuits and whether D3 receptors regulate specific prefrontal subnetworks remains unknown...
June 14, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28512247/targetable-t-type-calcium-channels-drive-glioblastoma
#7
Ying Zhang, Nichola Cruickshanks, Fang Yuan, Baomin Wang, Mary Pahuski, Julia Wulfkuhle, Isela Gallagher, Alexander F Koeppel, Sarah Hatef, Christopher Papanicolas, Jeongwu Lee, Eli E Bar, David Schiff, Stephen Turner, Emanuel F Petricoin, Lloyd S Gray, Roger Abounader
Glioblastoma stem-like cells (GSC) promote tumor initiation, progression and therapeutic resistance. Here we show how GSC can be targeted by the FDA approved drug mibefradil which inhibits the T-type calcium channel Cav3.2. This calcium channel was highly expressed in human GBM specimens and enriched in GSC. Analyses of the TCGA and REMBRANDT databases confirmed upregulation of Cav3.2 in a subset of tumors and showed that overexpression associated with worse prognosis. Mibefradil treatment or RNAi-mediated attenuation of Cav3...
May 16, 2017: Cancer Research
https://www.readbyqxmd.com/read/28498861/modulation-of-caveolins-integrins-and-plasma-membrane-repair-proteins-in-anthracycline-induced-heart-failure-in-rabbits
#8
Yasuhiro Ichikawa, Alice E Zemljic-Harpf, Zheng Zhang, M Dan McKirnan, Ana Maria Manso, Robert S Ross, H Kirk Hammond, Hemal H Patel, David M Roth
Anthracyclines are chemotherapeutic drugs known to induce heart failure in a dose-dependent manner. Mechanisms involved in anthracycline cardiotoxicity are an area of relevant investigation. Caveolins bind, organize and regulate receptors and signaling molecules within cell membranes. Caveolin-3 (Cav-3), integrins and related membrane repair proteins can function as cardioprotective proteins. Expression of these proteins in anthracycline-induced heart failure has not been evaluated. We tested the hypothesis that daunorubicin alters cardioprotective protein expression in the heart...
2017: PloS One
https://www.readbyqxmd.com/read/28475719/neuritin-enhances-synaptic-transmission-in-medial-prefrontal-cortex-in-mice-by-increasing-cav3-3-surface-expression
#9
Jun-Mei Lu, Dong-Dong Liu, Zhao-Yang Li, Chen Ling, Yan-Ai Mei
Neuritin is a neurotrophic factor involved in neural development and synaptic plasticity. However, its role in modulating synaptic transmission remains unclear. Here, we investigated the effects of neuritin on miniature excitatory postsynaptic currents (mEPSCs) and glutamate release in the medial prefrontal cortex (mPFC) in mice. Incubation of mPFC slices with neuritin for 45 min significantly increased mEPSC frequency and glutamate release as measured by high-performance liquid chromatography, which was mimicked by insulin and abrogated by an insulin receptor (IR) inhibitor...
May 4, 2017: Cerebral Cortex
https://www.readbyqxmd.com/read/28467171/down-regulation-of-t-type-cav3-2-channels-by-hyperpolarization-activated-cyclic-nucleotide-gated-channel-1-hcn1-evidence-of-a-signaling-complex
#10
Jing Fan, Maria A Gandini, Fang-Xiong Zhang, Lina Chen, Ivana A Souza, Gerald W Zamponi
Formation of complexes between ion channels is important for signal processing in the brain. Here we investigate the biochemical and biophysical interactions between HCN1 channels and Cav3.2 T-type channels. We found that HCN1 co-immunoprecipitated with Cav3.2 from lysates of either mouse brain or tsA-201 cells, with the HCN1 N-terminus associating with the Cav3.2 N-terminus. Cav3.2 channel activity appeared to be functionally regulated by HCN1. The expression of HCN1 induced a decrease in Cav3.2 Ba(2+) influx (IBa(2+)) along with altered channel kinetics and a depolarizing shift in activation gating...
May 3, 2017: Channels
https://www.readbyqxmd.com/read/28453798/caveolin-2-a-facultative-marker-of-unfavourable-prognosis-in-long-term-patency-rate-of-internal-thoracic-artery-grafts-used-in-coronary-artery-bypass-grafting-preliminary-report
#11
Agnieszka Malinska, Zuzanna Podemska, Patrycja Sujka-Kordowska, Wojciech Witkiewicz, Michal Nowicki, Bartlomiej Perek, Martin Witt
OBJECTIVES: Intimal hyperplasia leading to graft failure in patients undergoing coronary artery bypass grafting (CABG) is related to vascular smooth muscle cells (SMCs) proliferation. SMCs respond to a variety of mediators, the most important of which is platelet-derived growth factor (PDGF). The platelet-derived growth factor-induced cellular response has been shown to be mediated by caveolins. The aim of this study was to analyze CAV1-3 expression in internal thoracic artery (ITA) grafts used in CABG and correlate their expression with graft occlusion...
May 1, 2017: Interactive Cardiovascular and Thoracic Surgery
https://www.readbyqxmd.com/read/28450109/t-type-calcium-channels-but-not-cav3-2-in-the-peripheral-sensory-afferents-are-involved-in-acute-itch-in-mice
#12
Si-Fang Lin, Bing Wang, Feng-Ming Zhang, Yuan-Hui Fei, Jia-Hui Gu, Jie Li, Ling-Bo Bi, Xing-Jun Liu
T-type calcium channels are prominently expressed in primary nociceptive fibers and well characterized in pain processes. Although itch and pain share many similarities including primary sensory fibers, the function of T-type calcium channels on acute itch has not been explored. We investigated whether T-type calcium channels expressed within primary sensory fibers of mouse skin, especially Cav3.2 subtype, involve in chloroquine-, endothelin-1- and histamine-evoked acute itch using pharmacological, neuronal imaging and behavioral analyses...
June 10, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28438566/t-type-voltage-gated-calcium-channels-are-involved-in-endothelium-dependent-relaxation-of-mice-pulmonary-artery
#13
Guillaume Gilbert, Arnaud Courtois, Mathilde Dubois, Laure-Anne Cussac, Thomas Ducret, Philippe Lory, Roger Marthan, Jean-Pierre Savineau, Jean-François Quignard
In pulmonary arterial endothelial cells, Ca(2+) channels and intracellular Ca(2+)concentration ([Ca(2+)]i) control the release of vasorelaxant factors such as nitric oxide and are involved in the regulation of pulmonary arterial blood pressure. The present study was undertaken to investigate the implication of T-type voltage-gated Ca(2+)channels (T-VGCCs, Cav3.1 channel) in the endothelium-dependent relaxation of intrapulmonary arteries. Relaxation was quantified by means of a myograph in wild type and Cav3...
April 21, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/28431968/cannabinoid-cb1-and-cb2-receptors-differentially-modulate-l-and-t-type-ca-2-channels-in-rat-retinal-ganglion-cells
#14
Wen-Jing Qian, Ning Yin, Feng Gao, Yanying Miao, Qian Li, Fang Li, Xing-Huai Sun, Xiong-Li Yang, Zhongfeng Wang
Endocannabinoid signaling system is involved in regulating multiple neuronal functions in the central nervous system by activating G-protein coupled cannabinoid CB1 and CB2 receptors (CB1Rs and CB2Rs). Growing evidence has shown that CB1Rs and CB2Rs are extensively expressed in retinal ganglion cells (RGCs). Here, modulation of L- and T-types Ca(2+) channels by activating CB1Rs and CB2Rs in RGCs was investigated. Triple immunofluorescent staining showed that L-type subunit CaV1.2 was co-localized with T-type subunits (CaV3...
April 18, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28399450/synthesis-of-new-n3-substituted-dihydropyrimidine-derivatives-as-l-t-type-calcium-channel-blockers
#15
Mohamed Teleb, Fang-Xiong Zhang, Ahmed M Farghaly, Omaima M Aboul Wafa, Frank R Fronczek, Gerald W Zamponi, Hesham Fahmy
Cardiovascular diseases (CVDs) are the main cause of deaths worldwide. Up-to-date, hypertension is the most significant contributing factor to CVDs. Recent clinical studies recommend calcium channel blockers (CCBs) as effective treatment alone or in combination with other medications. Being the most clinically useful CCBs, 1,4-dihydropyridines (DHPs) attracted great interest in improving potency and selectivity. However, the short plasma half-life which may be attributed to the metabolic oxidation to the pyridine-counterparts is considered as a major limitation for this class...
July 7, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28393090/gender-specific-hippocampal-whole-genome-transcriptome-data-from-mice-lacking-the-cav2-3-r-type-or-cav3-2-t-type-voltage-gated-calcium-channel
#16
Anna Papazoglou, Christina Henseler, Andreas Lundt, Carola Wormuth, Julien Soos, Karl Broich, Dan Ehninger, Marco Weiergräber
Voltage-gated Ca(2+) channels are of central relevance in mediating numerous intracellular and transcellular processes including excitation-contraction coupling, excitation secretion-coupling, hormone and neurotransmitter release and gene expression. The Cav2.3 R-type Ca(2+) channel is a high-voltage activated channel which plays a crucial role in neurotransmitter release, long-term potentiation and hormone release. Furthermore, Cav2.3 R-type channels were reported to be involved in ictogenesis, epileptogenesis, fear behavior, sleep, pre-and postsynaptic integration and rhythmicity within the hippocampus...
June 2017: Data in Brief
https://www.readbyqxmd.com/read/28360836/genetic-tracing-of-cav3-2-t-type-calcium-channel-expression-in-the-peripheral-nervous-system
#17
Yinth A Bernal Sierra, Julia Haseleu, Alexey Kozlenkov, Valérie Bégay, Gary R Lewin
Characterizing the distinct functions of the T-type ion channel subunits Cav3.1, 3.2 or 3.3 has proven difficult due to their highly conserved amino-acid sequences and the lack of pharmacological blockers specific for each subunit. To precisely determine the expression pattern of the Cav3.2 channel in the nervous system we generated two knock-in mouse strains that express EGFP or Cre recombinase under the control of the Cav3.2 gene promoter. We show that in the brains of these animals, the Cav3.2 channel is predominantly expressed in the dentate gyrus of the hippocampus...
2017: Frontiers in Molecular Neuroscience
https://www.readbyqxmd.com/read/28330839/evolutionary-insights-into-t-type-ca-2-channel-structure-function-and-ion-selectivity-from-the-trichoplax-adhaerens-homologue
#18
Carolyn L Smith, Salsabil Abdallah, Yuen Yan Wong, Phuong Le, Alicia N Harracksingh, Liana Artinian, Arianna N Tamvacakis, Vincent Rehder, Thomas S Reese, Adriano Senatore
Four-domain voltage-gated Ca(2+) (Cav) channels play fundamental roles in the nervous system, but little is known about when or how their unique properties and cellular roles evolved. Of the three types of metazoan Cav channels, Cav1 (L-type), Cav2 (P/Q-, N- and R-type) and Cav3 (T-type), Cav3 channels are optimized for regulating cellular excitability because of their fast kinetics and low activation voltages. These same properties permit Cav3 channels to drive low-threshold exocytosis in select neurons and neurosecretory cells...
April 3, 2017: Journal of General Physiology
https://www.readbyqxmd.com/read/28253495/tacrolimus-triggers-transient-receptor-potential-vanilloid-1-dependent-relapse-of-pancreatitis-related-pain-in-mice
#19
Yuka Terada, Maho Tsubota, Hiiragi Sugo, Kohei Wakitani, Fumiko Sekiguchi, Kyoichi Wada, Mitsutaka Takada, Akira Oita, Atsufumi Kawabata
Transient receptor potential vanilloid-1 (TRPV1) expressed in nociceptors is directly phosphorylated and activated by protein kinase C, and involved in the signaling of pancreatic pain. On the other hand, Cav3.2 T-type Ca2+ channels expressed in nociceptors are functionally upregulated by phosphorylation with protein kinase A and also play a role in pancreatitis-related pain. Calcineurin, a phosphatase, negatively regulates various channel functions including TRPV1, and calcineurin inhibitor-induced pain syndrome by tacrolimus, a calcineurin inhibitor, used as an immunosuppressant, has been a clinical problem...
2017: Pharmacology
https://www.readbyqxmd.com/read/28145504/honeybee-locomotion-is-impaired-by-am-cav3-low-voltage-activated-ca-2-channel-antagonist
#20
M Rousset, C Collet, T Cens, F Bastin, V Raymond, I Massou, C Menard, J-B Thibaud, M Charreton, M Vignes, M Chahine, J C Sandoz, P Charnet
Voltage-gated Ca(2+) channels are key transducers of cellular excitability and participate in several crucial physiological responses. In vertebrates, 10 Ca(2+) channel genes, grouped in 3 families (CaV1, CaV2 and CaV3), have been described and characterized. Insects possess only one member of each family. These genes have been isolated in a limited number of species and very few have been characterized although, in addition to their crucial role, they may represent a collateral target for neurotoxic insecticides...
February 1, 2017: Scientific Reports
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