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https://www.readbyqxmd.com/read/28808020/kcne1-and-kcne3-modulate-kcnq1-channels-by-affecting-different-gating-transitions
#1
Rene Barro-Soria, Rosamary Ramentol, Sara I Liin, Marta E Perez, Robert S Kass, H Peter Larsson
KCNE β-subunits assemble with and modulate the properties of voltage-gated K(+) channels. In the heart, KCNE1 associates with the α-subunit KCNQ1 to generate the slowly activating, voltage-dependent potassium current (IKs) in the heart that controls the repolarization phase of cardiac action potentials. By contrast, in epithelial cells from the colon, stomach, and kidney, KCNE3 coassembles with KCNQ1 to form K(+) channels that are voltage-independent K(+) channels in the physiological voltage range and important for controlling water and salt secretion and absorption...
August 14, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28807015/genomic-upregulation-of-cardiac-cav1-2%C3%AE-and-ncx1-by-estrogen-in-women
#2
Rita Papp, Glenna C L Bett, Agnieszka Lis, Randall L Rasmusson, István Baczkó, András Varró, Guy Salama
BACKGROUND: Women have a higher risk of lethal arrhythmias than men in long QT syndrome type 2 (LQTS2), but the mechanisms remain uncertain due to the limited availability of healthy control human tissue. We have previously reported that in female rabbits, estrogen increases arrhythmia risk in drug-induced LQTS2 by upregulating L-type Ca(2+) (ICa,L) and sodium-calcium exchange (INCX) currents at the base of the epicardium by a genomic mechanism. This study investigates if the effects of estrogen on rabbit ICa,L and INCX apply to human hearts...
August 14, 2017: Biology of Sex Differences
https://www.readbyqxmd.com/read/28805023/onion-allium-cepa-l-peel-extract-ope-regulates-human-sperm-motility-via-protein-kinase-c-mediated-activation-of-the-human-voltage-gated-proton-channel
#3
M R Chae, S J Kang, K P Lee, B R Choi, H K Kim, J K Park, C Y Kim, S W Lee
Onion (Allium cepa L.) and quercetin protect against oxidative damage and have positive effects on multiple functional parameters of spermatozoa, including viability and motility. However, the associated underlying mechanisms of action have not yet been identified. The aim of this study was to investigate the effect of onion peel extract (OPE) on voltage-gated proton (Hv1) channels, which play a critical role in rapid proton extrusion. This process underlies a wide range of physiological processes, particularly male fertility...
August 13, 2017: Andrology
https://www.readbyqxmd.com/read/28802123/clathrodin-hymenidin-and-oroidin-and-their-synthetic-analogues-as-inhibitors-of-the-voltage-gated-potassium-channels
#4
Nace Zidar, Aleš Žula, Tihomir Tomašič, Marc Rogers, Robert W Kirby, Jan Tytgat, Steve Peigneur, Danijel Kikelj, Janez Ilaš, Lucija Peterlin Mašič
We have prepared three alkaloids from the Agelas sponges, clathrodin, hymenidin and oroidin, and a series of their synthetic analogues, and evaluated their inhibitory effect against six isoforms of the Kv1 subfamily of voltage-gated potassium channels, Kv1.1-Kv1.6, expressed in Chinese Hamster ovary (CHO) cells using automated patch clamp electrophysiology assay. The most potent inhibitor was the (E)-N-(3-(2-amino-1H-imidazol-4-yl)allyl)-4,5-dichloro-1H-pyrrole-2-carboxamide (6g) with IC50 values between 1...
August 7, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28801600/cav1-3-l-type-ca-2-channel-contributes-to-the-heartbeat-by-generating-a-dihydropyridine-sensitive-persistent-na-current
#5
Futoshi Toyoda, Pietro Mesirca, Stefan Dubel, Wei-Guang Ding, Joerg Striessnig, Matteo E Mangoni, Hiroshi Matsuura
The spontaneous activity of sinoatrial node (SAN) pacemaker cells is generated by a functional interplay between the activity of ionic currents of the plasma membrane and intracellular Ca(2+) dynamics. The molecular correlate of a dihydropyridine (DHP)-sensitive sustained inward Na(+) current (I st), a key player in SAN automaticity, is still unknown. Here we show that I st and the L-type Ca(2+) current (I Ca,L) share CaV1.3 as a common molecular determinant. Patch-clamp recordings of mouse SAN cells showed that I st is activated in the diastolic depolarization range, and displays Na(+) permeability and minimal inactivation and sensitivity to I Ca,L activators and blockers...
August 11, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28769585/%C3%AE-lipoic-acid-suppresses-neuronal-excitability-and-attenuates-colonic-hypersensitivity-to-colorectal-distention-in-diabetic-rats
#6
Yan Sun, Pan-Pan Yang, Zhen-Yuan Song, Yu Feng, Duan-Min Hu, Ji Hu, Guang-Yin Xu, Hong-Hong Zhang
AIM: Patients with long-standing diabetes often demonstrate intestinal dysfunction, characterized as constipation or colonic hypersensitivity. Our previous studies have demonstrated the roles of voltage-gated sodium channels NaV1.7 and NaV1.8 in dorsal root ganglion (DRG) in colonic hypersensitivity of rats with diabetes. This study was designed to determine roles of antioxidant α-lipoic acid (ALA) on sodium channel activities and colonic hypersensitivity of rats with diabetes. METHODS: Streptozotocin was used to induce diabetes in adult female rats...
2017: Journal of Pain Research
https://www.readbyqxmd.com/read/28758259/transient-receptor-potential-melastatin-4-channel-is-required-for-rat-dental-pulp-stem-cell-proliferation-and-survival
#7
T D Ngoc Tran, K E Stovall, T Suantawee, Y Hu, S Yao, L-J Yang, S Adisakwattana, H Cheng
OBJECTIVES: Investigate the role of the transient receptor potential melastatin 4 (TRPM4) channel in rat dental pulp stem cell (DPSC) proliferation and survival. MATERIALS AND METHODS: Immunofluorescence and FACS analysis were used to detect the stem cell marker CD90. Alizarin Red S and Oil Red O staining were used to identify osteoblast and adipocyte differentiation, respectively. To characterize TRPM4, patch-clamp recordings were obtained from single cells in the whole-cell configuration mode...
July 30, 2017: Cell Proliferation
https://www.readbyqxmd.com/read/28754781/nongenomic-modulation-of-the-large-conductance-voltage-and-ca-2-activated-k-channels-by-estrogen-a-novel-regulatory-mechanism-in-human-detrusor-smooth-muscle
#8
Kiril L Hristov, Shankar P Parajuli, Aaron Provence, Eric S Rovner, Georgi V Petkov
Estrogens have an important role in regulating detrusor smooth muscle (DSM) function. However, the underlying molecular and cellular mechanisms by which estrogens control human DSM excitability and contractility are not well known. Here, we used human DSM specimens from open bladder surgeries on 27 patients to elucidate the mechanism by which 17β-estradiol regulates large conductance voltage- and Ca(2+)-activated K(+) (BK) channels, the most prominent K(+) channels in human DSM We employed single BK channel recordings on inside-out excised membrane patches, perforated whole-cell patch-clamp on freshly isolated DSM cells, and isometric tension recordings on DSM-isolated strips to investigate the mechanism by which 17β-estradiol activates BK channels...
July 2017: Physiological Reports
https://www.readbyqxmd.com/read/28752895/development-of-resurgent-and-persistent-sodium-currents-in-mesencephalic-trigeminal-neurons
#9
Akifumi Enomoto, Soju Seki, Susumu Tanaka, Kohji Ishihama, Tadashi Yamanishi, Mikihiko Kogo, Suguru Hamada
Sodium channels play multiple roles in the formation of neural membrane properties in mesencephalic trigeminal (Mes V) neurons and in other neural systems. Mes V neurons exhibit conditional robust high-frequency spike discharges. As previously reported, resurgent and persistent sodium currents (INaR and INaP , respectively) may carry small currents at subthreshold voltages that contribute to generation of spike firing. These currents play an important role in maintaining and allowing high-frequency spike discharge during a burst...
July 28, 2017: Journal of Neuroscience Research
https://www.readbyqxmd.com/read/28751862/utp-gated-signaling-pathways-of-5-ht-release-from-bon-cells-as-a-model-of-human-enterochromaffin-cells
#10
Andromeda Liñán-Rico, Fernando Ochoa-Cortes, Alix Zuleta-Alarcon, Mazin Alhaj, Esmerina Tili, Josh Enneking, Alan Harzman, Iveta Grants, Sergio Bergese, Fievos L Christofi
Background: Enterochromaffin cells (EC) synthesize and release 5-HT and ATP to trigger or modulate gut neural reflexes and transmit information about visceral/pain sensation. Alterations in 5-HT signaling mechanisms may contribute to the pathogenesis of IBD or IBS, but the pharmacologic or molecular mechanisms modulating Ca(2+)-dependent 5-HT release are not understood. Previous studies indicated that purinergic signaling via ATP and ADP is an important mechanism in modulation of 5-HT release. However, EC cells also respond to UTP and UDP suggesting uridine triphosphate receptor and signaling pathways are involved as well...
2017: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/28749574/design-synthesis-pharmacological-evaluation-and-docking-studies-of-glun2b-selective-nmda-receptor-antagonists-with-a-benzo-7-annulen-7-amine-scaffold
#11
Sandeep Gawaskar, Louisa Temme, Julian A Schreiber, Dirk Schepmann, Alessandro Bonifazi, Dina Robaa, Wolfgang Sippl, Nathalie Strutz-Seebohm, Guiscard Seebohm, Bernhard Wünsch
Antagonists that selectively target GluN2B-subunit-containing N-methyl-d-aspartate (NMDA) receptors are of major interest for the treatment of various neurological disorders. In this study, relationships between variously substituted benzo[7]annulen-7-amines and their GluN2B affinity were investigated. 2-Nitro-5,6,8,9-tetrahydrobenzo[7]annulen-7-one (8) represents the central building block for the introduction of various substituents at the 2-position and various 7-amino moieties. N-(3-Phenylpropyl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-7-amines with a 2-NO2 (7 c), 2-Cl (15 c), or 2-OBn group (22 c) show very high GluN2B affinity (Ki =1...
July 27, 2017: ChemMedChem
https://www.readbyqxmd.com/read/28747464/lethal-digenic-mutations-in-the-k-channels-kir4-1-kcnj10-and-slack-kcnt1-associated-with-severe-disabling-seizures-and-neurodevelopmental-delay
#12
Sonia Majed Hasan, Ameera Balobaid, Alessandro Grottesi, Omar Dabbagh, Marta Cenciarini, Rifaat Rawashdeh, Afaf Al-Sagheir, Cecilia Bove, Lara Macchioni, Mauro Pessia, Mohammed Al-Owain, Maria Cristina D'Adamo
A 2-year-old boy presented profound developmental delay, failure to thrive, ataxia, hypotonia and tonic-clonic seizures that caused the death of the patient. Targeted and whole-exome sequencing revealed two heterozygous missense variants: a novel mutation in KCNJ10 gene that encodes for the inwardly-rectifying K(+) channel Kir4.1 and another previously characterized mutation in KCNT1 that encodes for the Na(+)-activated K(+) channel known as Slo2.2 or SLACK. The objectives of this study were to perform the clinical and genetic characterization of the proband and his family and to examine the functional consequence of the Kir4...
July 26, 2017: Journal of Neurophysiology
https://www.readbyqxmd.com/read/28744649/electrophysiological-features-of-single-store-operated-calcium-channels-in-hek-s4-cell-line-with-stable-stim1-protein-knockdown
#13
A V Shalygin, V A Vigont, L N Glushankova, O A Zimina, D O Kolesnikov, A Yu Skopin, E V Kaznacheeva
An important role in intracellular calcium signaling is played by store-operated channels activated by STIM proteins, calcium sensors of the endoplasmic reticulum. In stable STIM1 knockdown HEK S4 cells, single channels activated by depletion of intracellular calcium stores were detected by cell-attached patch-clamp technique and their electrophysiological parameters were described. Comparison of the properties of single channels in HEK293 and HEK S4 cells revealed no significant differences in their current-voltage curves, while regulation of store-operated calcium channels in these cell lines depended on the level of STIM1 expression...
July 26, 2017: Bulletin of Experimental Biology and Medicine
https://www.readbyqxmd.com/read/28744203/synaptic-ribbon-active-zones-in-cone-photoreceptors-operate-independently-from-one-another
#14
Justin J Grassmeyer, Wallace B Thoreson
Cone photoreceptors depolarize in darkness to release glutamate-laden synaptic vesicles. Essential to release is the synaptic ribbon, a structure that helps organize active zones by clustering vesicles near proteins that mediate exocytosis, including voltage-gated Ca(2+) channels. Cone terminals have many ribbon-style active zones at which second-order neurons receive input. We asked whether there are functionally significant differences in local Ca(2+) influx among ribbons in individual cones. We combined confocal Ca(2+) imaging to measure Ca(2+) influx at individual ribbons and patch clamp recordings to record whole-cell ICa in salamander cones...
2017: Frontiers in Cellular Neuroscience
https://www.readbyqxmd.com/read/28743763/a-key-role-for-peroxynitrite-mediated-inhibition-of-cardiac-erg-kv11-1-k-channels-in-carbon-monoxide-induced-proarrhythmic-early-afterdepolarizations
#15
Moza M Al-Owais, Nishani T Hettiarachchi, Hannah M Kirton, Matthew E Hardy, John P Boyle, Jason L Scragg, Derek S Steele, Chris Peers
Exposure to CO causes early afterdepolarization arrhythmias. Previous studies in rats have indicated that arrhythmias arose as a result of augmentation of the late Na(+) current. The purpose of the present study was to examine the basis for CO-induced arrhythmias in guinea pig myocytes in which action potentials (APs) more closely resemble those of human myocytes. Whole-cell current- and voltage-clamp recordings were made from isolated guinea pig myocytes as well as from human embryonic kidney 293 (HEK293) cells that express wild-type or a C723S mutant form of ether-a-go-go-related gene (ERG; Kv11...
July 25, 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/28739325/d242n-a-kv7-1-lqts-mutation-uncovers-a-key-residue-for-iks-voltage-dependence
#16
Cristina Moreno, Anna Oliveras, Chiara Bartolucci, Carmen Muñoz, Alicia de la Cruz, Diego A Peraza, Juan R Gimeno, Mercedes Martín-Martínez, Stefano Severi, Antonio Felipe, Pier D Lambiase, Teresa Gonzalez, Carmen Valenzuela
KV7.1 and KCNE1 co-assemble to give rise to the IKs current, one of the most important repolarizing currents of the cardiac action potential. Its relevance is underscored by the identification of >500 mutations in KV7.1 and, at least, 36 in KCNE1, that cause Long QT Syndrome (LQTS). The aim of this study was to characterize the biophysical and cellular consequences of the D242N KV7.1 mutation associated with the LQTS. The mutation is located in the S4 transmembrane segment, within the voltage sensor of the KV7...
July 22, 2017: Journal of Molecular and Cellular Cardiology
https://www.readbyqxmd.com/read/28736919/a-g326e-substitution-in-the-glutamate-gated-chloride-channel-3-glucl3-of-the-two-spotted-spider-mite-tetranychus-urticae-abolishes-the-agonistic-activity-of-macrocyclic-lactones
#17
Catherine Mermans, Wannes Dermauw, Sven Geibel, Thomas Van Leeuwen
BACKGROUND: The macrocyclic lactones abamectin and milbemectin are frequently used to control phytophagous mites such as Tetranychus urticae. Consequently, resistance has developed and was genetically linked with substitutions in the glutamate-gated chloride channel (GluCl) subunits TuGluCl1 and TuGluCl3. Here, we functionally validated a G326E substitution in TuGluCl3 by functional expression in Xenopus laevis oocytes followed by two-electrode voltage-clamp electrophysiology. RESULTS: Homomeric wild-type and mutated GluCl3 were successfully expressed...
July 24, 2017: Pest Management Science
https://www.readbyqxmd.com/read/28734073/differential-calcium-sensitivity-in-nav-1-5-mixed-syndrome-mutants
#18
Mena Abdelsayed, Alban-Elouen Baruteau, Karen Gibbs, Shubhayan Sanatani, Andrew D Krahn, Vincent Probst, Peter C Ruben
INTRODUCTION: Inherited arrhythmias may arise from mutations in the SCN5a gene, which encodes the cardiac voltage-gated sodium channel, NaV 1.5. Mutants in NaV 1.5 result in Brugada Syndrome (BrS1), Long-QT Syndrome (LQT3), or mixed syndromes (an overlap of BrS1/LQT3). Exercise is a potential arrhythmogenic trigger in mixed syndromes. We sought to determine the effects of elevated cytosolic calcium, common during exercise, in mixed syndrome NaV 1.5 mutants. METHODS: We used whole-cell patch-clamp to assess the biophysical properties of NaV 1...
July 22, 2017: Journal of Physiology
https://www.readbyqxmd.com/read/28733893/effects-of-new-generation-tmem16a-inhibitors-on-calcium-activated-chloride-currents-in-rabbit-urethral-interstitial-cells-of-cajal
#19
Stephen Fedigan, Eamonn Bradley, Timothy Webb, Roddy J Large, Mark A Hollywood, Keith D Thornbury, Noel G McHale, Gerard P Sergeant
Interstitial cells of Cajal (ICC) isolated from the rabbit urethra exhibit Ca(2+)-activated Cl(-) currents (I ClCa) that are important for the development of urethral tone. Here, we examined if TMEM16A (ANO1) contributed to this activity by examining the effect of "new-generation" TMEM16A inhibitors, CACCinh-A01 and T16Ainh-A01, on I ClCa recorded from freshly isolated rabbit urethral ICC (RUICC) and on contractions of intact strips of rabbit urethra smooth muscle. Real-time quantitative PCR experiments demonstrated that TMEM16A was highly expressed in rabbit urethra smooth muscle, in comparison to TMEM16B and TMEM16F...
July 21, 2017: Pflügers Archiv: European Journal of Physiology
https://www.readbyqxmd.com/read/28732557/a-negative-slope-conductance-of-the-persistent-sodium-current-prolongs-subthreshold-depolarizations
#20
Cesar C Ceballos, Antonio C Roque, Ricardo M Leão
Neuronal subthreshold voltage-dependent currents determine membrane properties such as the input resistance (Rin) and the membrane time constant (τm) in the subthreshold range. In contrast with classical cable theory predictions, the persistent sodium current (INaP), a non-inactivating mode of the voltage-dependent sodium current, paradoxically increases Rin and τm when activated. Furthermore, this current amplifies and prolongs synaptic currents in the subthreshold range. Here, using a computational neuronal model, we showed that the creation of a region of negative slope conductance by INaP activation is responsible for these effects and the ability of the negative slope conductance to amplify and prolong Rin and τm relies on the fast activation of INaP...
July 18, 2017: Biophysical Journal
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