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https://www.readbyqxmd.com/read/28391996/molecular-mechanisms-underlying-pimaric-acid-induced-modulation-of-voltage-gated-k-channels
#1
Kazuho Sakamoto, Yoshiaki Suzuki, Hisao Yamamura, Susumu Ohya, Katsuhiko Muraki, Yuji Imaizumi
Voltage-gated K(+) (KV) channels, which control firing and shape of action potentials in excitable cells, are supposed to be potential therapeutic targets in many types of diseases. Pimaric acid (PiMA) is a unique opener of large conductance Ca(2+)-activated K(+) channel. Here, we report that PiMA modulates recombinant rodent KV channel activity. The enhancement was significant at low potentials (<0 mV) but not at more positive potentials. Application of PiMA significantly shifted the voltage-activation relationships (V1/2) of rodent KV1...
March 8, 2017: Journal of Pharmacological Sciences
https://www.readbyqxmd.com/read/28365825/inhibition-of-inwardly-rectifying-kir2-x-channels-by-the-novel-anti-cancer-agent-gambogic-acid-depends-on-both-pore-block-and-pip2-interference
#2
Daniel Scherer, Benedikt Schworm, Claudia Seyler, Panagiotis Xynogalos, Eberhard P Scholz, Dierk Thomas, Hugo A Katus, Edgar Zitron
The caged xanthone gambogic acid (GA) is a novel anti-cancer agent which exhibits anti-proliferative, anti-inflammatory and cytotoxic effects in many types of cancer tissues. In a recent phase IIa study, GA exhibits a favourable safety profile. However, limited data are available concerning its interaction with cardiac ion channels. Heteromeric assembly of Kir2.x channels underlies the cardiac inwardly rectifying IK1 current which is responsible for the stabilization of the diastolic resting membrane potential...
April 2, 2017: Naunyn-Schmiedeberg's Archives of Pharmacology
https://www.readbyqxmd.com/read/28315276/the-sigma-1-receptor-a-therapeutic-target-for-the-treatment-of-als
#3
Timur A Mavlyutov, Erin M Baker, Tasher M Losenegger, Jaimie R Kim, Brian Torres, Miles L Epstein, Arnold E Ruoho
The membrane bound 223 amino acid Sigma-1 Receptor (S1R) serves as a molecular chaperone and functional regulator of many signaling proteins. Spinal cord motor neuron activation occurs, in part, via large ventral horn cholinergic synapses called C-boutons/C-terminals. Chronic excitation of motor neurons and alterations in C-terminals has been associated with Amyotrophic Lateral Sclerosis (ALS ). The S1R has an important role in regulating motor neuron function. High levels of the S1R are localized in postsynaptic endoplasmic reticulum (ER) subsurface cisternae within 10-20 nm of the plasma membrane that contain muscarinic type 2 acetylcholine receptors (M2AChR), calcium activated potassium channels (Kv2...
2017: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/28280416/nortriptyline-a-tricyclic-antidepressant-inhibits-voltage-dependent-k-channels-in-coronary-arterial-smooth-muscle-cells
#4
Sung Eun Shin, Hongliang Li, Han Sol Kim, Hye Won Kim, Mi Seon Seo, Kwon-Soo Ha, Eun-Taek Han, Seok-Ho Hong, Amy L Firth, Il-Whan Choi, Young Min Bae, Won Sun Park
We demonstrated the effect of nortriptyline, a tricyclic antidepressant drug and serotonin reuptake inhibitor, on voltage-dependent K(+) (Kv) channels in freshly isolated rabbit coronary arterial smooth muscle cells using a whole-cell patch clamp technique. Nortriptyline inhibited Kv currents in a concentration-dependent manner, with an apparent IC50 value of 2.86±0.52 µM and a Hill coefficient of 0.77±0.1. Although application of nortriptyline did not change the activation curve, nortriptyline shifted the inactivation current toward a more negative potential...
March 2017: Korean Journal of Physiology & Pharmacology
https://www.readbyqxmd.com/read/28260386/measurement-of-hanatoxin-induced-membrane-thinning-with-lamellar-x-ray-diffraction
#5
Meng-Hsuan Hsieh, Yu-Shuan Shiau, Horng-Huei Liou, U-Ser Jeng, Ming-Tao Lee, Kuo-Long Lou
Membrane perturbation induced by cysteine-rich peptides is a crucial biological phenomenon but scarcely investigated, in particular with effective biophysical-chemical methodologies. Hanatoxin (HaTx), a 35-residue polypeptide from spider venom, works as an inhibitor of drk1 (Kv2.1) channels, most likely by interacting with the voltage-sensor. However, how this water-soluble peptide modifies the gating remains poorly understood, as the voltage sensor was proposed to be deeply embedded within the bilayer. To see how HaTx interacts with phospholipid bilayers, we observe the toxin-induced perturbation on POPC/DOPG-membranes through measurements of the change in membrane thickness...
March 21, 2017: Langmuir: the ACS Journal of Surfaces and Colloids
https://www.readbyqxmd.com/read/28247497/centipede-venom-peptide-ssmtx-i-with-two-intramolecular-disulfide-bonds-shows-analgesic-activities-in-animal-models
#6
Ying Wang, Xiaojie Li, Meifeng Yang, Chunyun Wu, Zhirong Zou, Jing Tang, Xinwang Yang
Pain is a major symptom of many diseases and results in enormous pressures on human body or society. Currently, clinically used analgesic drugs, including opioids and nonsteroidal anti-inflammatory drugs, have adverse reactions, and thus, the development of new types of analgesic drug candidates is urgently needed. Animal venom peptides have proven to have potential as new types of analgesic medicine. In this research, we describe the isolation and characterization of an analgesic peptide from the crude venom of centipede, Scolopendra subspinipes mutilans...
March 1, 2017: Journal of Peptide Science: An Official Publication of the European Peptide Society
https://www.readbyqxmd.com/read/28143758/hanatoxin-inserts-into-phospholipid-membranes-without-pore-formation
#7
Kuo-Long Lou, Meng-Hsuan Hsieh, Wei-Jung Chen, Yu-Che Cheng, Jia-Nan Jian, Ming-Tao Lee, Tsang-Lang Lin, Yu-Shuan Shiau, Horng-Huei Liou
Hanatoxin (HaTx), a 35-residue polypeptide from spider venom, functions as an inhibitor of Kv2.1 channels by interacting with phospholipids prior to affecting the voltage-sensor. However, how this water-soluble peptide modifies the gating remains poorly understood, as the voltage-sensor is deeply embedded within the bilayer. To determine how HaTx interacts with phospholipid bilayers, in this study, we examined the toxin-induced partitioning of liposomal membranes. HPLC-results from high-speed spin-down vesicles with HaTx demonstrated direct binding...
January 29, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28139741/independent-movement-of-the-voltage-sensors-in-kv2-1-kv6-4-heterotetramers
#8
Elke Bocksteins, Dirk J Snyders, Miguel Holmgren
Heterotetramer voltage-gated K(+) (KV) channels KV2.1/KV6.4 display a gating charge-voltage (QV) distribution composed by two separate components. We use state dependent chemical accessibility to cysteines substituted in either KV2.1 or KV6.4 to assess the voltage sensor movements of each subunit. By comparing the voltage dependences of chemical modification and gating charge displacement, here we show that each gating charge component corresponds to a specific subunit forming the heterotetramer. The voltage sensors from KV6...
January 31, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28065942/neuregulin-1-erbb-module-in-c-bouton-synapses-on-somatic-motor-neurons-molecular-compartmentation-and-response-to-peripheral-nerve-injury
#9
Anna Casanovas, Sara Salvany, Víctor Lahoz, Olga Tarabal, Lídia Piedrafita, Raimundo Sabater, Sara Hernández, Jordi Calderó, Josep E Esquerda
The electric activity of lower motor neurons (MNs) appears to play a role in determining cell-vulnerability in MN diseases. MN excitability is modulated by cholinergic inputs through C-type synaptic boutons, which display an endoplasmic reticulum-related subsurface cistern (SSC) adjacent to the postsynaptic membrane. Besides cholinergic molecules, a constellation of proteins involved in different signal-transduction pathways are clustered at C-type synaptic sites (M2 muscarinic receptors, Kv2.1 potassium channels, Ca(2+) activated K(+) [SK] channels, and sigma-1 receptors [S1R]), but their collective functional significance so far remains unknown...
January 9, 2017: Scientific Reports
https://www.readbyqxmd.com/read/27928161/novel-kcnb1-mutation-associated-with-non-syndromic-intellectual-disability
#10
Xénia Latypova, Naomichi Matsumoto, Cécile Vinceslas-Muller, Stéphane Bézieau, Bertrand Isidor, Noriko Miyake
Potassium voltage-gated channel subfamily B member 1 (KCNB1) encodes Kv2.1 potassium channel of crucial role in hippocampal neuron excitation homeostasis. KCNB1 mutations are known to cause early-onset infantile epilepsy. To date, 10 KCNB1 mutations have been described in 11 patients. Using whole-exome sequencing, we identified a novel de novo missense (c.1132G>C, p.V378L) KCNB1 mutation in a patient with global developmental delay, intellectual disability, severe speech impairment, but no episode of epilepsy until the lastly examined age of 6 years old...
April 2017: Journal of Human Genetics
https://www.readbyqxmd.com/read/27916464/subtype-specific-block-of-voltage-gated-k-channels-by-%C3%AE-conopeptides
#11
Enrico Leipold, Florian Ullrich, Markus Thiele, Alesia A Tietze, Heinrich Terlau, Diana Imhof, Stefan H Heinemann
The neurotoxic cone snail peptide μ-GIIIA specifically blocks skeletal muscle voltage-gated sodium (NaV1.4) channels. The related conopeptides μ-PIIIA and μ-SIIIA, however, exhibit a wider activity spectrum by also inhibiting the neuronal NaV channels NaV1.2 and NaV1.7. Here we demonstrate that those μ-conopeptides with a broader target range also antagonize select subtypes of voltage-gated potassium channels of the KV1 family: μ-PIIIA and μ-SIIIA inhibited KV1.1 and KV1.6 channels in the nanomolar range, while being inactive on subtypes KV1...
January 22, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/27884958/activity-dependent-redistribution-of-kv2-1-ion-channels-on-rat-spinal-motoneurons
#12
Shannon H Romer, Adam S Deardorff, Robert E W Fyffe
Homeostatic plasticity occurs through diverse cellular and synaptic mechanisms, and extensive investigations over the preceding decade have established Kv2.1 ion channels as key homeostatic regulatory elements in several central neuronal systems. As in these cellular systems, Kv2.1 channels in spinal motoneurons (MNs) localize within large somatic membrane clusters. However, their role in regulating motoneuron activity is not fully established in vivo. We have previously demonstrated marked Kv2.1 channel redistribution in MNs following in vitro glutamate application and in vivo peripheral nerve injury (Romer et al...
November 2016: Physiological Reports
https://www.readbyqxmd.com/read/27810559/interaction-site-for-the-inhibition-of-tarantula-jingzhaotoxin-xi-on-voltage-gated-potassium-channel-kv2-1
#13
Huai Tao, Xia Chen, Meichun Deng, Yucheng Xiao, Yuanyuan Wu, Zhonghua Liu, Sainan Zhou, Yingchun He, Songping Liang
Jingzhaotoxin-XI (JZTX-XI) is a 34-residue peptide from the Chinese tarantula Chilobrachys jingzhao venom that potently inhibits both voltage-gated sodium channel Nav1.5 and voltage-gated potassium channel Kv2.1. In the present study, we further showed that JZTX-XI blocked Kv2.1 currents with the IC50 value of 0.39 ± 0.06 μM. JZTX-XI significantly shifted the current-voltage (I-V) curves and normalized conductance-voltage (G-V) curves of Kv2.1 channel to more depolarized voltages. Ala-scanning mutagenesis analyses demonstrated that mutants I273A, F274A, and E277A reduced toxin binding affinity by 10-, 16-, and 18-fold, respectively, suggesting that three common residues (I273, F274, E277) in the Kv2...
December 15, 2016: Toxicon: Official Journal of the International Society on Toxinology
https://www.readbyqxmd.com/read/27798188/oxidation-of-kcnb1-potassium-channels-causes-neurotoxicity-and-cognitive-impairment-in-a-mouse-model-of-traumatic-brain-injury
#14
Wei Yu, Randika Parakramaweera, Shavonne Teng, Manasa Gowda, Yashsavi Sharad, Smita Thakker-Varia, Janet Alder, Federico Sesti
The delayed rectifier potassium (K(+)) channel KCNB1 (Kv2.1), which conducts a major somatodendritic current in cortex and hippocampus, is known to undergo oxidation in the brain, but whether this can cause neurodegeneration and cognitive impairment is not known. Here, we used transgenic mice harboring human KCNB1 wild-type (Tg-WT) or a nonoxidable C73A mutant (Tg-C73A) in cortex and hippocampus to determine whether oxidized KCNB1 channels affect brain function. Animals were subjected to moderate traumatic brain injury (TBI), a condition characterized by extensive oxidative stress...
October 26, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/27760355/extracellular-linkers-completely-transplant-the-voltage-dependence-from-kv1-2-ion-channels-to-kv2-1
#15
Fredrik Elinder, Michael Madeja, Hugo Zeberg, Peter Århem
The transmembrane voltage needed to open different voltage-gated K (Kv) channels differs by up to 50 mV from each other. In this study we test the hypothesis that the channels' voltage dependences to a large extent are set by charged amino-acid residues of the extracellular linkers of the Kv channels, which electrostatically affect the charged amino-acid residues of the voltage sensor S4. Extracellular cations shift the conductance-versus-voltage curve, G(V), by interfering with these extracellular charges...
October 18, 2016: Biophysical Journal
https://www.readbyqxmd.com/read/27734968/the-anticonvulsant-retigabine-suppresses-neuronal-kv2-mediated-currents
#16
Jeroen I Stas, Elke Bocksteins, Camilla S Jensen, Nicole Schmitt, Dirk J Snyders
Enhancement of neuronal M-currents, generated through KV7.2-KV7.5 channels, has gained much interest for its potential in developing treatments for hyperexcitability-related disorders such as epilepsy. Retigabine, a KV7 channel opener, has proven to be an effective anticonvulsant and has recently also gained attention due to its neuroprotective properties. In the present study, we found that the auxiliary KCNE2 subunit reduced the KV7.2-KV7.3 retigabine sensitivity approximately 5-fold. In addition, using both mammalian expression systems and cultured hippocampal neurons we determined that low μM retigabine concentrations had 'off-target' effects on KV2...
October 13, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27729411/functional-antagonism-of-voltage-gated-k-channel-%C3%AE-subunits-in-the-developing-brain-ventricular-system
#17
Hongyuan Shen, Elke Bocksteins, Igor Kondrychyn, Dirk Snyders, Vladimir Korzh
The brain ventricular system is essential for neurogenesis and brain homeostasis. Its neuroepithelial lining effects these functions, but the underlying molecular pathways remain to be understood. We found that the potassium channels expressed in neuroepithelial cells determine the formation of the ventricular system. The phenotype of a novel zebrafish mutant characterized by denudation of neuroepithelial lining of the ventricular system and hydrocephalus is mechanistically linked to Kcng4b, a homologue of the 'silent' voltage-gated potassium channel α-subunit Kv6...
November 15, 2016: Development
https://www.readbyqxmd.com/read/27638047/comparison-of-voltage-gated-k-currents-in-arterial-myocytes-with-heterologously-expressed-k-v-subunits
#18
Robert H Cox, Samantha Fromme
We have shown that three components contribute to functional voltage gated K(+) (K v) currents in rat small mesenteric artery myocytes: (1) Kv1.2 plus Kv1.5 with Kvβ1.2 subunits, (2) Kv2.1 probably associated with Kv9.3 subunits, and (3) Kv7.4 subunits. To confirm and address subunit stoichiometry of the first two, we have compared the biophysical properties of K v currents in small mesenteric artery myocytes with those of Kv subunits heterologously expressed in HEK293 cells using whole cell voltage clamp methods...
December 2016: Cell Biochemistry and Biophysics
https://www.readbyqxmd.com/read/27562026/physiological-roles-of-kv2-channels-in-entorhinal-cortex-layer-ii-stellate-cells-revealed-by-guangxitoxin-1e
#19
Christoph Hönigsperger, Maximiliano J Nigro, Johan F Storm
KEY POINTS: Kv2 channels underlie delayed-rectifier potassium currents in various neurons, although their physiological roles often remain elusive. Almost nothing is known about Kv2 channel functions in medial entorhinal cortex (mEC) neurons, which are involved in representing space, memory formation, epilepsy and dementia. Stellate cells in layer II of the mEC project to the hippocampus and are considered to be space-representing grid cells. We used the new Kv2 blocker Guangxitoxin-1E (GTx) to study Kv2 functions in these neurons...
February 1, 2017: Journal of Physiology
https://www.readbyqxmd.com/read/27320844/dromedary-immune-response-and-specific-kv2-1-antibody-generation-using-a-specific-immunization-approach
#20
Rym Hassiki, Alain J Labro, Zakaria Benlasfar, Cécile Vincke, Mahmoud Somia, Mohamed El Ayeb, Serge Muyldermans, Dirk J Snyders, Balkiss Bouhaouala-Zahar
Voltage-gated potassium (Kv) channels form cells repolarizing power and are commonly expressed in excitable cells. In non-excitable cells, Kv channels such as Kv2.1 are involved in cell differentiation and growth. Due to the involvement of Kv2.1 in several physiological processes, these channels are promising therapeutic targets. To develop Kv2.1 specific antibody-based channel modulators, we applied a novel approach and immunized a dromedary with heterologous Ltk- cells that overexpress the mouse Kv2.1 channel instead of immunizing with channel protein fragments...
December 2016: International Journal of Biological Macromolecules
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