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https://www.readbyqxmd.com/read/29022505/pharmacological-targeting-of-neuronal-kv7-2-3-channels-a-focus-on-chemotypes-and-receptor-sites
#1
Francesco Miceli, Maria Virginia Soldovieri, Paolo Ambrosino, Laura Manocchio, Alessandro Medoro, Ilaria Mosca, Maurizio Taglialatela
BACKGROUND: The Kv7 (KCNQ) subfamily of voltage-gated potassium channels consists of 5 members (Kv7.1-5) each showing a characteristic tissue distribution and physiological roles. Given their functional heterogeneity, Kv7 channels represent important pharmacological targets for development of new drugs for neuronal, cardiac and metabolic diseases. OBJECTIVE: In the present manuscript, we focus on describing the pharmacological relevance and the potential therapeutic applications of drugs acting on neuronally-expressed Kv7...
October 12, 2017: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/29022503/the-renal-outer-medullary-potassium-channel-romk-an-intriguing-pharmacological-target-for-an-innovative-class-of-diuretic-drugs
#2
Vincenzo Calderone, Alma Martelli, Eugenia Piragine, Valentina Citi, Lara Testai, Maria Cristina Breschi
In the last four decades, the several classes of diuretics, currently available for clinical use, have been the first line option for the therapy of widespread cardiovascular and non-cardiovascular diseases. Diuretic drugs generally exhibit an overall favourable risk/benefit balance. However, they are not devoid of side effects. In particular, all the classes of diuretics cause alteration of potassium homeostasis. In recent years, understanding of the physiological role of the renal outer medullary potassium (ROMK) channels, has shown an intriguing pharmacological target for developing an innovative class of diuretic agents: the ROMK inhibitors...
October 12, 2017: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/29022502/pathophysiological-role-of-mitochondrial-potassium-channels-and-their-modulation-by-drugs
#3
Valentina Citi, Vincenzo Calderone, Alma Martelli, Maria Cristina Breschi, Lara Testai
Mitochondria play a central role in ATP-generating processes. Indeed, in mammalian tissues, up to 90% of ATP is generated by mitochondria through the process of oxidative phosphorylation; furthermore, mitochondria are involved in multiple signal transduction pathways. A rapidly expanding body of literature has confirmed that mitochondria play a pivotal role in apoptosis, cardio- and neuro-protection, and various neurodegenerative disorders, ranging from Parkinson's to Alzheimer's disease. It is evident that mitochondria are also the targets of multiple drugs; some of these are exactly designed to influence mitochondrial function, while others have primary targets in other cellular locations but may interact with mitochondria because of the presence of numerous targets on this organelle...
October 12, 2017: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/29022263/cardiac-ischemia-reperfusion-injury-the-beneficial-effects-of-exercise
#4
Juliana Pereira Borges, Karine da Silva Verdoorn
Cardiac ischemia reperfusion injury (IRI) occurs when the myocardium is revascularized after an episode of limited or absent blood supply. Many changes, including free radical production, calcium overload, protease activation, altered membrane lipids and leukocyte activation, contribute to IRI-induced myocardium damage. Aerobic exercise is the only countermeasure against IRI that can be sustained on a regular basis in clinical practice. Interestingly, both short-term (3-5 days) and long-term (several weeks) exercise increase myocardial tolerance, reduce infarct size area and arrhythmias induced by IRI...
2017: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/29021804/calcium-and-calmodulin-are-involved-in-nitric-oxide-induced-adventitious-rooting-of-cucumber-under-simulated-osmotic-stress
#5
Lijuan Niu, Jian Yu, Weibiao Liao, Jihua Yu, Meiling Zhang, Mohammed M Dawuda
Osmotic stress is a major form of abiotic stress that adversely affects growth and development of plants and subsequently reduces yield and quality of crops. In this study, the effect of nitric oxide (NO) and calcium (Ca(2+)) on the process of adventitious rooting in cucumber (Cucumis sativus L.) under simulated osmotic stress was investigated. The results revealed that the effect of exogenous NO and Ca(2+) in promoting the development of adventitious roots in cucumber seedlings under simulated osmotic stress was dose-dependent, with a maximal biological response at 10 μM NO donor nitroprusside (SNP) or 200 μM Ca(2+)...
2017: Frontiers in Plant Science
https://www.readbyqxmd.com/read/29021305/predicting-the-functional-impact-of-kcnq1-variants-of-unknown-significance
#6
Bian Li, Jeffrey L Mendenhall, Brett M Kroncke, Keenan C Taylor, Hui Huang, Derek K Smith, Carlos G Vanoye, Jeffrey D Blume, Alfred L George, Charles R Sanders, Jens Meiler
BACKGROUND: An emerging standard-of-care for long-QT syndrome uses clinical genetic testing to identify genetic variants of the KCNQ1 potassium channel. However, interpreting results from genetic testing is confounded by the presence of variants of unknown significance for which there is inadequate evidence of pathogenicity. METHODS AND RESULTS: In this study, we curated from the literature a high-quality set of 107 functionally characterized KCNQ1 variants. Based on this data set, we completed a detailed quantitative analysis on the sequence conservation patterns of subdomains of KCNQ1 and the distribution of pathogenic variants therein...
October 2017: Circulation. Cardiovascular Genetics
https://www.readbyqxmd.com/read/29020060/phosphatidylinositol-4-5-bisphosphate-is-required-for-kcnq1-kcne1-channel-function-but-not-anterograde-trafficking
#7
Alice A Royal, Andrew Tinker, Stephen C Harmer
The slow delayed-rectifier potassium current (IKs) is crucial for human cardiac action potential repolarization. The formation of IKs requires co-assembly of the KCNQ1 α-subunit and KCNE1 β-subunit, and mutations in either of these subunits can lead to hereditary long QT syndrome types 1 and 5, respectively. It is widely recognised that the KCNQ1/KCNE1 (Q1/E1) channel requires phosphatidylinositol-4,5-bisphosphate (PIP2) binding for function. We previously identified a cluster of basic residues in the proximal C-terminus of KCNQ1 that form a PIP2/phosphoinositide binding site...
2017: PloS One
https://www.readbyqxmd.com/read/29019366/moderation-of-hyperuricemia-in-rats-via-consuming-walnut-protein-hydrolysate-diet-and-identification-of-new-antihyperuricemic-peptides
#8
Qingyong Li, Xiaoyan Kang, Chuanchao Shi, Yujuan Li, Kaustav Majumder, Zhengxiang Ning, Jiaoyan Ren
In this study, walnut meal hydrolysates (WMH) and dephenolized walnut meal hydrolysates (DWMH) were found to effectively decrease the serum uric acid level and protect the renal function in potassium oxonate-induced hyperuricemic rats in vivo as well as inhibit xanthine oxidase in vitro. Two novel antihyperuricemic peptides including WPPKN (640.8 Da) and ADIYTE (710.7 Da) were purified from DWMH via Sephadex G-15 gel filtration and reverse-phase high-performance liquid chromatography and identified by LC-ESI-MS/MS...
October 11, 2017: Food & Function
https://www.readbyqxmd.com/read/29018452/kv1-3-channel-blockade-modulates-the-effector-function-of-b-cells-in-granulomatosis-with-polyangiitis
#9
Judith Land, Lucas L Lintermans, Coen A Stegeman, Ernesto J Muñoz-Elías, Eric J Tarcha, Shawn P Iadonato, Peter Heeringa, Abraham Rutgers, Wayel H Abdulahad
B cells are central to the pathogenesis of granulomatosis with polyangiitis (GPA), exhibiting both (auto)antibody-dependent and -independent properties. Class-switched memory B cells in particular are a major source of pathogenic autoantibodies. These cells are characterized by high expression levels of Kv1.3 potassium channels, which may offer therapeutic potential for Kv1.3 blockade. In this study, we investigated the effect of the highly potent Kv1.3 blocker ShK-186 on B cell properties in GPA in vitro. Circulating B cell subsets were determined from 33 GPA patients and 17 healthy controls (HCs)...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/29016852/potassium-channel-dysfunction-underlies-purkinje-neuron-spiking-abnormalities-in-spinocerebellar-ataxia-type-2
#10
James M Dell'Orco, Stefan M Pulst, Vikram G Shakkottai
Alterations in Purkinje neuron firing often accompany ataxia, but the molecular basis for these changes is poorly understood. In a mouse model of spinocerebellar ataxia type 2 (SCA2), a progressive reduction in Purkinje neuron firing frequency accompanies cell atrophy. We investigated the basis for altered Purkinje neuron firing in SCA2. A reduction in the expression of large-conductance calcium-activated potassium (BK) channels and Kv3.3 voltage-gated potassium channels accompanies the inability of Purkinje neurons early in disease to maintain repetitive spiking...
October 15, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28994652/mechanism-of-activation-at-the-selectivity-filter-of-the-kcsa-k-channel
#11
Florian T Heer, David J Posson, Wojciech Wojtas-Niziurski, Crina M Nimigean, Simon Bernèche
Potassium channels are opened by ligands and/or membrane potential. In voltage-gated K(+) channels and the prokaryotic KcsA channel, conduction is believed to result from opening of an intracellular constriction that prevents ion entry into the pore. On the other hand, numerous ligand-gated K(+) channels lack such gate, suggesting that they may be activated by a change within the selectivity filter, a narrow region at the extracellular side of the pore. Using molecular dynamics simulations and electrophysiology measurements, we show that ligand-induced conformational changes in the KcsA channel removes steric restraints at the selectivity filter, thus resulting in structural fluctuations, reduced K(+) affinity, and increased ion permeation...
October 10, 2017: ELife
https://www.readbyqxmd.com/read/28993838/delta-opioid-receptor-expression-and-function-in-primary-afferent-somatosensory-neurons
#12
Amaury François, Grégory Scherrer
The functional diversity of primary afferent neurons of the dorsal root ganglia (DRG) generates a variety of qualitatively and quantitatively distinct somatosensory experiences, from shooting pain to pleasant touch. In recent years, the identification of dozens of genetic markers specifically expressed by subpopulations of DRG neurons has dramatically improved our understanding of this diversity and provided the tools to manipulate their activity and uncover their molecular identity and function. Opioid receptors have long been known to be expressed by discrete populations of DRG neurons, in which they regulate cell excitability and neurotransmitter release...
October 10, 2017: Handbook of Experimental Pharmacology
https://www.readbyqxmd.com/read/28993731/small-and-intermediate-calcium-activated-potassium-channel-openers-improve-rat-endothelial-and-erectile-function
#13
Simon G Comerma-Steffensen, Ingrid Carvacho, Elise R Hedegaard, Ulf Simonsen
Modulation of endothelial calcium-activated potassium (KCa) channels has been proposed as an approach to restore endothelial function. The present study investigated whether novel openers of KCa channels with small (KCa2.x) and intermediate (KCa3.1) conductance, NS309 and NS4591, improve endothelium-dependent relaxation and erectile function. Rat corpus cavernosum (CC) strips were mounted for isometric tension recording and processed for immunoblotting. Mean arterial pressure (MAP), intracavernosal pressure (ICP), and electrocardiographic (ECG) measurements were conducted in anesthetized rats...
2017: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/28993452/macrolides-blunt-aldosterone-biosynthesis-a-proof-of-concept-study-in-kcnj5-mutated-adenoma-cells-ex-vivo
#14
Brasilina Caroccia, Selene Prisco, Teresa Maria Seccia, Maria Piazza, Giuseppe Maiolino, Gian Paolo Rossi
Aldosterone-producing adenoma (APA), a major subtype of primary hyperaldosteronism, the main curable cause of human endocrine hypertension, involves somatic mutations in the potassium channel Kir3.4 (KCNJ5) in 30% to 70% of cases, typically the more florid phenotypes. Because KCNJ5 mutated channels were reported to be specifically sensitive to inhibition by macrolide antibiotics, which concentration dependently blunts aldosterone production in HAC15 transfected with the G151R and L168R mutated channel, we herein tested the effect of clarithromycin on aldosterone synthesis and secretion in a pure population of aldosterone-secreting cells obtained by immunoseparation (CD56(+) cells) from APA tissues with/without the 2 most common KCNJ5 mutations...
October 9, 2017: Hypertension
https://www.readbyqxmd.com/read/28993277/structure-folding-and-stability-of-a-minimal-homologue-from-anemonia-sulcata-of-the-sea-anemone-potassium-channel-blocker-shk
#15
Bankala Krishnarjuna, Christopher A MacRaild, Punnepalli Sunanda, Rodrigo A V Morales, Steve Peigneur, Jason Macrander, Heidi H Yu, Marymegan Daly, Srinivasarao Raghothama, Vikas Dhawan, Satendra Chauhan, Jan Tytgat, Michael W Pennington, Raymond S Norton
Peptide toxins elaborated by sea anemones target various ion-channel sub-types. Recent transcriptomic studies of sea anemones have identified several novel candidate peptides, some of which have cysteine frameworks identical to those of previously reported sequences. One such peptide is AsK132958, which was identified in a transcriptomic study of Anemonia sulcata and has a cysteine framework similar to that of ShK from Stichodactyla helianthus, but is six amino acid residues shorter. We have determined the solution structure of this novel peptide using NMR spectroscopy...
October 6, 2017: Peptides
https://www.readbyqxmd.com/read/28993158/high-potency-block-of-kir4-1-channels-by-pentamidine-molecular-basis
#16
Iván A Aréchiga-Figueroa, Leticia G Marmolejo-Murillo, Meng Cui, Mayra Delgado-Ramírez, Marcel A G van der Heyden, José A Sánchez-Chapula, Aldo A Rodríguez-Menchaca
Inward rectifier potassium (Kir) channels are expressed in almost all mammalian tissues and contribute to a wide range of physiological processes. Kir4.1 channel expression is found in the brain, inner ear, eye, and kidney. Loss-of-function mutations in the pore-forming Kir4.1 subunit cause an autosomal recessive disorder characterized by epilepsy, ataxia, sensorineural deafness and tubulopathy (SeSAME/EST syndrome). Despite its importance in physiological and pathological conditions, pharmacological research of Kir4...
October 6, 2017: European Journal of Pharmacology
https://www.readbyqxmd.com/read/28992755/drug-mediated-shortening-of-action-potentials-in-lqts2-human-induced-pluripotent-stem-cell-derived-cardiomyocytes
#17
Gary Duncan, Karl Firth, Vinoj George, Minh Duc Hoang, Andrew Staniforth, Godfrey Smith, Chris Denning
Cardiomyocytes (CMs) derived from human induced pluripotent stem cells (hiPSCs) are now a well-established modality for modelling genetic disorders of the heart. This is especially so for long QT syndrome (LQTS), which is caused by perturbation of ion channel function, and can lead to fainting, malignant arrhythmias and sudden cardiac death. LQTS2 is caused by mutations in KCNH2, a gene whose protein product contributes to IKr (also known as HERG), which is the predominant repolarising potassium current in CMs...
October 9, 2017: Stem Cells and Development
https://www.readbyqxmd.com/read/28992529/a-comprehensive-structural-model-for-the-human-kcnq1-kcne1-ion-channel
#18
Horia Jalily Hasani, Marawan Ahmed, Khaled Barakat
The voltage-gated KCNQ1/KCNE1 potassium ion channel complex, forms the slow delayed rectifier (IKs) current in the heart, which plays an important role in heart signaling. The importance of KCNQ1/KCNE1 channel's function is further implicated by the linkage between loss-of-function and gain-of-function mutations in KCNQ1 or KCNE1, and long QT syndromes, congenital atrial fibrillation, and short QT syndrome. Also, KCNQ1/KCNE1 channels are an off-target for many non-cardiovascular drugs, leading to fatal cardiac irregularities...
September 29, 2017: Journal of Molecular Graphics & Modelling
https://www.readbyqxmd.com/read/28992433/kcnq-encoded-potassium-channels-as-therapeutic-targets
#19
Vincenzo Barrese, Jennifer B Stott, Iain A Greenwood
Kv7 channels are voltage-gated potassium channels encoded by KCNQ genes that have a considerable physiological impact in many cell types. This reliance upon Kv7 channels for normal cellular function, as well as the existence of hereditary disorders caused by mutations to KCNQ genes, means that pharmacological targeting of these channels has broad appeal. Consequently, a plethora of chemical entities that modulate Kv7 channel activity have been developed. Moreover, Kv7 channels are influenced by many disparate intracellular mediators and trafficking processes, making upstream targeting an appealing prospect for therapeutic development...
October 6, 2017: Annual Review of Pharmacology and Toxicology
https://www.readbyqxmd.com/read/28988768/crosstalk-between-kcnk3-mediated-ion-current-and-adrenergic-signaling-regulates-adipose-thermogenesis-and-obesity
#20
Yi Chen, Xing Zeng, Xuan Huang, Sara Serag, Clifford J Woolf, Bruce M Spiegelman
Adrenergic stimulation promotes lipid mobilization and oxidation in brown and beige adipocytes, where the harnessed energy is dissipated as heat in a process known as adaptive thermogenesis. The signaling cascades and energy-dissipating pathways that facilitate thermogenesis have been extensively described, yet little is known about the counterbalancing negative regulatory mechanisms. Here, we identify a two-pore-domain potassium channel, KCNK3, as a built-in rheostat negatively regulating thermogenesis. Kcnk3 is transcriptionally wired into the thermogenic program by PRDM16, a master regulator of thermogenesis...
September 30, 2017: Cell
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