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T-type calcium channel

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https://www.readbyqxmd.com/read/29126879/mechanical-stretch-increases-l-type-calcium-channel-stability-in-cardiomyocytes-through-a-polycystin-1-akt-dependent-mechanism
#1
A Córdova-Casanova, I Olmedo, J A Riquelme, G Barrientos, G Sánchez, T G Gillette, S Lavandero, M Chiong, P Donoso, Z Pedrozo
The L-type calcium channel (LTCC) is an important determinant of cardiac contractility. Therefore, changes in LTCC activity or protein levels could be expected to affect cardiac function. Several studies describing LTCC regulation are available, but only a few examine LTCC protein stability. Polycystin-1 (PC1) is a mechanosensor that regulates heart contractility and is involved in mechanical stretch-induced cardiac hypertrophy. PC1 was originally described as an unconventional Gi/o protein-coupled receptor in renal cells...
November 7, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/29116786/discovery-of-a-potent-selective-t-type-calcium-channel-blocker-as-a-drug-candidate-for-the-treatment-of-generalized-epilepsies
#2
Olivier Bezençon, Bibia Heidmann, Romain Siegrist, Simon Stamm, Sylvia Richard, Davide Pozzi, Olivier Corminboeuf, Catherine Roch, Melanie Kessler, Eric A Ertel, Isabelle Reymond, Thomas Pfeifer, Ruben de Kanter, Michael Toeroek-Schafroth, Luca G Moccia, Jacques Mawet, Richard Moon, Markus Rey, Bruno Capeleto, Elvire Fournier
We report here the discovery and pharmacological characterization of N-(1-benzyl-1H-pyrazol-3-yl)-2-phenylacetamide derivatives as potent, selective, brain-penetrating T-type calcium channel blockers. Optimization focused mainly on solubility, brain penetration, and search for an aminopyrazole metabolite that would be negative in an Ames test. This resulted in the preparation and complete characterization of compound 66b (ACT-709478), which has been selected as clinical candidate.
November 8, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29100477/activation-of-anoctamin-1-limits-pulmonary-endothelial-cell-proliferation-via-p38-mapk-dependent-apoptosis
#3
Ayed M Allawzi, Alexander Vang, Richard T Clements, Bong Sook Jhun, Nouaying R Kue, Thomas J Mancini, Amy K Landi, Dmitry Terentyev, Jin O-Uchi, Suzy A Comhair, Serpil C Erzurum, Gaurav Choudhary
Hyperproliferative endothelial cells (ECs) play an important role in the pathogenesis of PAH. Anoctamin-1 (Ano1), a calcium activated chloride channel, can regulate cell proliferation and cell cycle in multiple cell types. However, the expression and function of Ano1 in the pulmonary endothelium is unknown. We examined whether Ano1 was expressed in pulmonary ECs and if altering Ano1 activity would affect EC survival. Expression and localization of Ano1 in rat lung microvascular ECs (RLMVECs) was assessed using immunoblot, immunofluorescence, and subcellular fractionation...
November 3, 2017: American Journal of Respiratory Cell and Molecular Biology
https://www.readbyqxmd.com/read/29082441/deletion-of-t-type-calcium-channels-cav3-1-or-cav3-2-attenuates-endothelial-dysfunction-in-aging-mice
#4
Anne D Thuesen, Kenneth Andersen, Kristina S Lyngsø, Mark Burton, Charlotte Brasch-Andersen, Paul M Vanhoutte, Pernille B L Hansen
Impairment of endothelial function with aging is accompanied by reduced nitric oxide (NO) production. T-type Cav3.1 channels augment nitric oxide and co-localize with eNOS. Therefore, the hypothesis was that T-type channels contribute to the endothelial dysfunction of aging. Endothelial function was determined in mesenteric arteries (perfusion) and aortae (isometric contraction) of young and old wild-type (WT), Cav3.1, and Cav3.2 knockout mice. NO production was measured by fluorescence imaging in mesenteric arteries...
October 29, 2017: Pflügers Archiv: European Journal of Physiology
https://www.readbyqxmd.com/read/29074257/discovery-and-evaluation-of-cav3-2-selective-t-type-calcium-channel-blockers
#5
Olivier Bezençon, Luboš Remeň, Sylvia Richard, Catherine Roch, Melanie Kessler, Eric A Ertel, Richard Moon, Jacques Mawet, Thomas Pfeifer, Bruno Capeleto
We identified and characterized a series of pyrrole amides as potent, selective Cav3.2-blockers. This series culminated with the identification of pyrrole amides 13b and 26d, with excellent potencies and/or selectivities toward the Cav3.1- and Cav3.3-channels. These compounds display poor physicochemical and DMPK properties, making their use difficult for in vivo applications. Nevertheless, they are well-suited for in vitro studies.
September 30, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29073181/modulation-of-t-type-ca2-channels-by-lavender-and-rosemary-extracts
#6
Chaymae El Alaoui, Jean Chemin, Taoufiq Fechtali, Philippe Lory
Medicinal plants represent a significant reservoir of unexplored substances for early-stage drug discovery. Of interest, two flowering Mediterranean plants have been used for thousands of years for their beneficial effects on nervous disorders, including anxiety and mood. However, the therapeutic potential of these plants regarding their ability to target ion channels and neuronal excitability remains largely unknown. Towards this goal, we have investigated the ability of Lavender and Rosemary to modulate T-type calcium channels (TTCCs)...
2017: PloS One
https://www.readbyqxmd.com/read/29070417/milestones-to-the-discovery-of-t-type-calcium-channel-blockers-for-the-treatment-of-generalized-epilepsies
#7
Olivier Bezençon, Romain Siegrist, Bibia Heidmann, Davide Pozzi, Simon Stamm, Luboš Remeň, Sylvia Richard, Lloyd Simons, Rick Gaston, Dennis Downing, Corinna Grisostomi, Catherine Roch, Melanie Kessler, John Gatfield, Richard Moon, Thomas Pfeifer, Johannes Mosbacher, Isabelle Reymond, Eric A Ertel, Ruben de Kanter, Bruno Capeleto, Elvire Fournier, Markus Rey, Luca Moccia, Michael Toeroek-Schafroth, René Roscher, Benno Schindelholz
We describe the discovery and optimization of new, brain-penetrant T-type calcium channel blockers. We present optimized compounds with excellent efficacy in a rodent model of generalized absence-like epilepsy. Along the fine optimization of a chemical series with a pharmacological target located in the CNS (target potency, brain penetration, and solubility), we successfully identified an Ames negative aminopyrazole as putative metabolite of this compound series. Our efforts culminated in the selection of compound 20, which was elected as a preclinical candidate...
October 25, 2017: Chimia
https://www.readbyqxmd.com/read/29066309/discovery-and-evaluation-of-cav3-1-selective-t-type-calcium-channel-blockers
#8
Olivier Bezençon, Luboš Remeň, Sylvia Richard, Catherine Roch, Melanie Kessler, Richard Moon, Jacques Mawet, Eric A Ertel, Thomas Pfeifer, Bruno Capeleto
We identified and characterized a series of pyrazole amides as potent, selective Cav3.1-blockers. This series culminated with the identification of pyrazole amides 5a and 12d, with excellent potencies and/or selectivities toward the Cav3.2- and Cav3.3-channels. This compound displays poor DMPK properties, making its use difficult for in vivo applications. Nevertheless, this compound as well as analogous ones are well-suited for in vitro studies.
October 3, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29052595/corrigendum-hydrogen-sulfide-induced-itch-requires-activation-of-cav3-2-t-type-calcium-channel-in-mice
#9
Xue-Long Wang, Bin Tian, Ya Huang, Xiao-Yan Peng, Li-Hua Chen, Jun-Cheng Li, Tong Liu
This corrects the article DOI: 10.1038/srep16768.
October 20, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29038363/moderate-exercise-training-does-not-prevent-the-reduction-in-myocardial-l-type-ca-2-channels-protein-expression-at-obese-rats
#10
Vitor L da Silva, Ana P Lima-Leopoldo, Artur J T Ferron, Jóctan P Cordeiro, Paula P Freire, Dijon H S de Campos, Carlos R Padovani, Mário M Sugizaki, Antonio C Cicogna, André S Leopoldo
Authors have showed that obesity implicates cardiac dysfunction associated with myocardial L-type calcium channels (LTCCs) activity impairments, as well as moderate exercise training (MET) seems to be an important therapeutic tool. We tested the hypothesis that MET promotes improvements on LTCCS activity and protein expression at obesity induced by unsaturated high-fat diets, which could represent a protective effects against development of cardiovascular damage. Male Wistar rats were randomized in control (C, n = 40), which received a standard diet and obese (Ob; n = 40), which received high-fat diet...
October 2017: Physiological Reports
https://www.readbyqxmd.com/read/29036189/inhibition-of-cug-binding-protein-1-and-activation-of-caspases-are-critically-involved-in-piperazine-derivative-bk10007s-induced-apoptosis-in-hepatocellular-carcinoma-cells
#11
Ju-Ha Kim, Hee Young Kwon, Dong Hoon Ryu, Min-Ho Nam, Bum Sang Shim, Jin Han Kim, Jae Yeol Lee, Sung-Hoon Kim
Though piperazine derivative BK10007S was known to induce apoptosis in pancreatic cancer xenograft model as a T-type CaV3.1 a1G isoform calcium channel blocker, its underlying antitumor mechanism still remains unclear so far. Thus, in the present study, the antitumor mechanism of BK10007S was elucidated in hepatocellular carcinoma cells (HCCs). Herein, BK10007S showed significant cytotoxicity by 3-[4,5-2-yl]-2,5-diphenyltetra-zolium bromide (MTT) assay and anti-proliferative effects by colony formation assay in HepG2 and SK-Hep1 cells...
2017: PloS One
https://www.readbyqxmd.com/read/29024660/amyloid-beta-peptides-block-new-synapse-assembly-by-nogo-receptor-mediated-inhibition-of-t-type-calcium-channels
#12
Yanjun Zhao, Sivaprakash Sivaji, Michael C Chiang, Haadi Ali, Monica Zukowski, Sareen Ali, Bryan Kennedy, Alex Sklyar, Alice Cheng, Zihan Guo, Alexander K Reed, Ravindra Kodali, Jennifer Borowski, Georgia Frost, Patrick Beukema, Zachary P Wills
Compelling evidence links amyloid beta (Aβ) peptide accumulation in the brains of Alzheimer's disease (AD) patients with the emergence of learning and memory deficits, yet a clear understanding of the events that drive this synaptic pathology are lacking. We present evidence that neurons exposed to Aβ are unable to form new synapses, resulting in learning deficits in vivo. We demonstrate the Nogo receptor family (NgR1-3) acts as Aβ receptors mediating an inhibition of synapse assembly, plasticity, and learning...
October 11, 2017: Neuron
https://www.readbyqxmd.com/read/28980722/calcium-signaling-of-in-situ-chondrocytes-in-articular-cartilage-under-compressive-loading-roles-of-calcium-sources-and-cell-membrane-ion-channels
#13
Mengxi Lv, Yilu Zhou, Xingyu Chen, Lin Han, Liyun Wang, X Lucas Lu
Mechanical loading on articular cartilage can induce many physical and chemical stimuli on chondrocytes residing in the extracellular matrix (ECM). Intracellular calcium ([Ca(2+) ]i ) signaling is among the earliest responses of chondrocytes to physical stimuli, but the [Ca(2+) ]i signaling of in situ chondrocytes in loaded cartilage is not fully understood due to the technical challenges in [Ca(2+) ]i imaging of chondrocytes in a deforming ECM. This study developed a novel bi-directional microscopy loading device that enables the record of transient [Ca(2+) ]i responses of in situ chondrocytes in loaded cartilage...
October 5, 2017: Journal of Orthopaedic Research: Official Publication of the Orthopaedic Research Society
https://www.readbyqxmd.com/read/28974495/prenatal-hypoxia-induced-dysfunction-in-cerebral-arteries-of-offspring-rats
#14
Jiaqi Tang, Na Li, Xueyi Chen, Qinqin Gao, Xiuwen Zhou, Yingying Zhang, Bailin Liu, Miao Sun, Zhice Xu
BACKGROUND: Hypoxia during pregnancy could cause abnormal development and lead to increased risks of vascular diseases in adults. This study determined angiotensin II (AII)-mediated vascular dysfunction in offspring middle cerebral arteries (MCA). METHODS AND RESULTS: Pregnant rats were subjected to hypoxia. Vascular tension in offspring MCA by AII with or without inhibitors, calcium channel activities, and endoplasmic reticulum calcium stores were tested. Whole-cell patch clamping was used to investigate voltage-dependent calcium channel currents...
October 3, 2017: Journal of the American Heart Association
https://www.readbyqxmd.com/read/28974111/in-vitro-neurotoxicity-by-ropivacaine-is-reduced-by-silencing-cav3-3-t-type-calcium-subunits-in-neonatal-rat-sensory-neurons
#15
Xianjie Wen, Hua Liang, Heng Li, Weiming Ou, Han-Bing Wang, Hongzhen Liu, Shijie Li
Neurotoxicity of local anaesthetics has been alerted by more and more peoples. Cav3.1 and Cav3.2 T-type calcium channels were closely related with local anaesthetics toxicity. However, the role of Cav3.3, another subtype of the T-type calcium channel, on the neurotoxicity induced by local anaesthetics remains unclear. CaMKIIγ is a kind of multifunctional kinase and associated with a variety of physiological and pathological process. T-type calcium channel is closely related with CaMKIIγ. Up-regulation CaMKIIγ can increase T-type currents at the dorsal root ganglia (DRG)...
October 3, 2017: Artificial Cells, Nanomedicine, and Biotechnology
https://www.readbyqxmd.com/read/28972185/calmodulin-regulates-cav3-t-type-channels-at-their-gating-brake
#16
Jean Chemin, Valentina Taiakina, Arnaud Monteil, Michael Piazza, Wendy Guan, Robert F Stephens, Ashraf Kitmitto, Zhiping P Pang, Annette C Dolphin, Edward Perez-Reyes, Thorsten Dieckmann, Joseph Guy Guillemette, J David Spafford
Calcium (Cav1 and Cav2) and sodium channels possess homologous CaM-binding motifs, known as IQ motifs in their C-termini, which associate with calmodulin (CaM), a universal calcium sensor. Cav3 T-type channels, which serve as pacemakers of the mammalian brain and heart, lack a C-terminal IQ motif. We illustrate that T-type channels associate with CaM using co-immunoprecipitation experiments and single particle cryo-electron microscopy. We demonstrate that protostome invertebrate (LCav3) and human Cav3.1, Cav3...
September 25, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28949006/calcium-influx-through-trpv4-channels-modulates-the-adherens-contacts-between-retinal-microvascular-endothelial-cells
#17
Tam T T Phuong, Sarah N Redmon, Oleg Yarishkin, Jacob M Winter, Dean Y Li, David Križaj
KEY POINTS: Endothelial cells employ transient receptor potential isoform 4 (TRPV4) channels to sense ambient mechanical and chemical stimuli. In retinal microvascular endothelial cells, TRPV4 channels regulate calcium homeostasis, cytoskeletal signalling and the organization of adherens junctional contacts. Intracellular calcium increases induced by TRPV4 agonists include a significant contribution from calcium release from internal stores. Activation of TRPV4 channels regulates retinal endothelial barriers in vitro and in vivo...
November 15, 2017: Journal of Physiology
https://www.readbyqxmd.com/read/28942482/effects-of-seasonal-acclimatization-on-thermal-tolerance-of-inward-currents-in-roach-rutilus-rutilus-cardiac-myocytes
#18
Ahmed Badr, Hanna Korajoki, El-Sabry Abu-Amra, Mohamed F El-Sayed, Matti Vornanen
To test the hypothesis of temperature-dependent deterioration of electrical excitability (TDEE) (Vornanen, J Exp Biol 219:1941-1952, 2016), the role of sodium (I Na) and calcium (I Ca) currents in heat tolerance of cardiac excitability was examined in a eurythermic fish, the roach (Rutilus rutilus). Densities of cardiac I Ca and I Na and their acute heat tolerance were measured in winter-acclimatized (WiR) and summer-acclimatized (SuR) fish maintained in the laboratory at 4 ± 1 and 18 ± 1 °C, respectively...
September 23, 2017: Journal of Comparative Physiology. B, Biochemical, Systemic, and Environmental Physiology
https://www.readbyqxmd.com/read/28934223/ursodeoxycholic-acid-prevents-ventricular-conduction-slowing-and-arrhythmia-by-restoring-t-type-calcium-current-in-fetuses-during-cholestasis
#19
Oladipupo Adeyemi, Anita Alvarez-Laviada, Francisca Schultz, Effendi Ibrahim, Michael Trauner, Catherine Williamson, Alexey V Glukhov, Julia Gorelik
BACKGROUND: Increased maternal serum bile acid concentrations in intrahepatic cholestasis of pregnancy (ICP) are associated with fetal cardiac arrhythmias. Ursodeoxycholic acid (UDCA) has been shown to demonstrate anti-arrhythmic properties via preventing ICP-associated cardiac conduction slowing and development of reentrant arrhythmias, although the cellular mechanism is still being elucidated. METHODS: High-resolution fluorescent optical mapping of electrical activity and electrocardiogram measurements were used to characterize effects of UDCA on one-day-old neonatal and adult female Langendorff-perfused rat hearts...
2017: PloS One
https://www.readbyqxmd.com/read/28916261/differential-involvement-of-l-and-t-type-ca-2-channels-store-operated-calcium-channel-trpc-and-rho-kinase-signaling-pathway-s-in-pgf2%C3%AE-induced-contractions-in-myometrium-of-non-pregnant-and-pregnant-buffaloes-bubalus-bubalis
#20
Abhishek Sharma, Udayraj P Nakade, Pooja Jaitley, Vipin Sharma, Soumen Choudhury, Satish Kumar Garg
This study unravels the differential involvement of calcium signaling pathway(s) in PGF2α-induced contractions in myometrium of non-pregnant and pregnant buffaloes. Compared to the myometrium of pregnant animals, myometrium of non-pregnant buffaloes was more sensitive to PGF2α-induced contractile effect as manifested by the changes in mean integral tension (MIT) and tonicity. However, phasic contraction was significantly more in myometrium of pregnant animals. The uterotonic effect of PGF2α was dependent on extracellular Ca(2+) and its influx through nifedipine-sensitive L-type Ca(2+) channels both in non-pregnant and pregnant animals, but T-type Ca(2+) channels play an additional role during pregnancy...
September 12, 2017: Prostaglandins & Other Lipid Mediators
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