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https://www.readbyqxmd.com/read/29047147/case-control-pharmacogenetic-study-of-hcn1-hcn2-variants-and-genetic-generalized-epilepsies
#1
Shu-Zhi Wu, Hua Ye, Xiao-Guo Yang, Zhi-Li Lu, Qiang Qu, Jian Qu
Epilepsy is a common complex neurological disorder, and some forms are resistant to drug treatment. The HCN1/HCN2 genes encode hyperpolarization-activated cyclic nucleotide-gated channels, which play important roles in the electrophysiology of neurons. We investigated the association between HCN1/HCN2 variants and drug resistance or the risk of genetic generalized epilepsies (GGEs). We used matrix-assisted laser desorption/ionization time-of-flight mass spectrometry to assess nine variants of HCN1/HCN2 in 284 healthy participants and 483 GGEs (279 drug-responsive, 204 drug-resistant)...
October 19, 2017: Clinical and Experimental Pharmacology & Physiology
https://www.readbyqxmd.com/read/28962131/effect-of-mhcn2-gene-modification-on-chronotropic-relevant-receptors-in-bmscs-co-cultured-with-atrial-myocytes
#2
Chandong Ding, Cuicui Yang, Quanxia Cao, Xiaoxia Zhu, Jianming Zhang, Wen Zhang, Yongping Wang, Long Li
Currently, the mechanism of the chronotropic ability of stem cells modified to express the hyperpolarization-activated cyclic nucleotide-gated (HCN) gene remains to be elucidated. The present study assessed the effects of mouse (m)HCN2 gene modification on the expression of chronotropic relevant receptors, adrenergic receptor β1 (Adrb1) and cholinergic receptor muscarinic M2 (Chrm2), in bone marrow stromal cells (BMSCs) co-cultured with atrial myocytes. BMSCs were divided into the following four groups: i) BMSCs transfected with the mHCN2 gene and co-cultured with atrial myocytes for 48 h (TF + CO); ii) respective transfection (TF); iii) respective co-culture (CO); and iv) the control group without treatment (CTL)...
September 2017: Experimental and Therapeutic Medicine
https://www.readbyqxmd.com/read/28954930/hyperpolarization-activated-cyclic-nucleotide-gated-2-hcn2-ion-channels-drive-pain-in-mouse-models-of-diabetic-neuropathy
#3
Christoforos Tsantoulas, Sergio Laínez, Sara Wong, Ishita Mehta, Bruno Vilar, Peter A McNaughton
Diabetic patients frequently suffer from continuous pain that is poorly treated by currently available analgesics. We used mouse models of type 1 and type 2 diabetes to investigate a possible role for the hyperpolarization-activated cyclic nucleotide-gated 2 (HCN2) ion channels as drivers of diabetic pain. Blocking or genetically deleting HCN2 channels in small nociceptive neurons suppressed diabetes-associated mechanical allodynia and prevented neuronal activation of second-order neurons in the spinal cord in mice...
September 27, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28950029/investigating-cyclic-nucleotide-and-cyclic-dinucleotide-binding-to-hcn-channels-by-surface-plasmon-resonance
#4
Sebastien Hayoz, Purushottam B Tiwari, Grzegorz Piszczek, Aykut Üren, Tinatin I Brelidze
Hyperpolarization-activated cyclic nucleotide-modulated (HCN) channels control cardiac and neuronal rhythmicity. HCN channels contain cyclic nucleotide-binding domain (CNBD) in their C-terminal region linked to the pore-forming transmembrane segment with a C-linker. The C-linker couples the conformational changes caused by the direct binding of cyclic nucleotides to the HCN pore opening. Recently, cyclic dinucleotides were shown to antagonize the effect of cyclic nucleotides in HCN4 but not in HCN2 channels...
2017: PloS One
https://www.readbyqxmd.com/read/28871229/gabapentin-modulates-hcn4-channel-voltage-dependence
#5
Han-Shen Tae, Kelly M Smith, A Marie Phillips, Kieran A Boyle, Melody Li, Ian C Forster, Robert J Hatch, Robert Richardson, David I Hughes, Brett A Graham, Steven Petrou, Christopher A Reid
Gabapentin (GBP) is widely used to treat epilepsy and neuropathic pain. There is evidence that GBP can act on hyperpolarization-activated cation (HCN) channel-mediated Ih in brain slice experiments. However, evidence showing that GBP directly modulates HCN channels is lacking. The effect of GBP was tested using two-electrode voltage clamp recordings from human HCN1, HCN2, and HCN4 channels expressed in Xenopus oocytes. Whole-cell recordings were also made from mouse spinal cord slices targeting either parvalbumin positive (PV(+)) or calretinin positive (CR(+)) inhibitory neurons...
2017: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/28864772/mechanism-for-the-inhibition-of-the-camp-dependence-of-hcn-ion-channels-by-the-auxiliary-subunit-trip8b
#6
John R Bankston, Hannah A DeBerg, Stefan Stoll, William N Zagotta
TRIP8b, an accessory subunit of hyperpolarization-activated cyclic nucleotide-gated (HCN) ion channels, alters both the cell surface expression and cyclic nucleotide dependence of these channels. However, the mechanism by which TRIP8b exerts these dual effects is still poorly understood. Besides binding to the carboxy-terminal tripeptide of HCN channels, TRIP8b also binds directly to the cyclic nucleotide-binding domain (CNBD). That interaction, which requires a small central portion of TRIP8b termed TRIP8bcore, is both necessary and sufficient for reducing the cAMP-dependent regulation of HCN channels...
September 1, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28777258/knockdown-of-long-noncoding-antisense-rna-brain-derived-neurotrophic-factor-attenuates-hypoxia-reoxygenation-induced-nerve-cell-apoptosis-through-the-bdnf-trkb-pi3k-akt-signaling-pathway
#7
Jian-Bin Zhong, Xie Li, Si-Ming Zhong, Jiu-Di Liu, Chi-Bang Chen, Xiao-Yan Wu
Brain-derived neurotrophic factor (BDNF) plays an important role in neuronal cell apoptosis. The antisense RNA of brain-derived neurotrophic factor (BDNF-AS) is a natural antisense transcript that is transcribed opposite the gene that encodes BDNF. The aim of this study was to determine whether knockdown of BDNF-AS can suppress hypoxia/reoxygenation (H/R)-induced neuronal cell apoptosis and whether this is mediated by the BDNF-TrkB-PI3K/Akt pathway. We detected the expression of BDNF and BDNF-AS in brain tissue from 20 patients with cerebral infarction and five patients with other diseases (but no cerebral ischemia)...
September 27, 2017: Neuroreport
https://www.readbyqxmd.com/read/28767511/protein-kinase-a-regulates-inflammatory-pain-sensitization-by-modulating-hcn2-channel-activity-in-nociceptive-sensory-neurons
#8
Stefan Herrmann, Hamsa Rajab, Irina Christ, Christoph Schirdewahn, Daniel Höfler, Michael J M Fischer, Ariane Bruno, Stefanie Fenske, Christian Gruner, Felix Kramer, Tassilo Wachsmann, Christian Wahl-Schott, Juliane Stieber, Martin Biel, Andreas Ludwig
Several studies implicated cyclic adenosine monophosphate (cAMP) as an important second messenger for regulating nociceptor sensitization, but downstream targets of this signaling pathway which contribute to neuronal plasticity are not well understood. We used a Cre/loxP-based strategy to disable the function of either HCN2 or PKA selectively in a subset of peripheral nociceptive neurons and analyzed the nociceptive responses in both transgenic lines. A near-complete lack of sensitization was observed in both mutant strains when peripheral inflammation was induced by an intradermal injection of 8br-cAMP...
October 2017: Pain
https://www.readbyqxmd.com/read/28666417/identifying-differential-mir-and-gene-consensus-patterns-in-peripheral-blood-of-patients-with-cardiovascular-diseases-from-literature-data
#9
Agnė Šatrauskienė, Rokas Navickas, Aleksandras Laucevičius, Heinrich J Huber
BACKGROUND: Numerous recent studies suggest the potential of circulating MicroRNAs (miRs) in peripheral blood samples as diagnostic or prognostic markers for coronary artery disease (CAD), acute coronary syndrome (ACS) and heart failure (HF). However, literature often remains inconclusive regarding as to which markers are most indicative for which of the above diseases. This shortcoming is mainly due to the lack of a systematic analyses and absence of information on the functional pathophysiological role of these miRs and their target genes...
June 30, 2017: BMC Cardiovascular Disorders
https://www.readbyqxmd.com/read/28642118/current-state-of-the-art-for-cardiac-arrhythmia-gene-therapy
#10
REVIEW
J Kevin Donahue
Cardiac arrhythmias are a leading cause of morbidity and mortality. Currently available therapeutic options lack sufficient efficacy and safety. Gene therapy has been proposed for treatment of cardiac arrhythmias. This review will discuss the current state of development for arrhythmia gene therapy. So far, all published studies are short-term, proof-of-concept animal studies. Potential replacement of cardiac pacemakers has been shown for combination gene therapy using the HCN2 gene and either the gene for adenylate cyclase, the skeletal muscle isoform of the sodium channel, or a dominant negative mutant of the potassium channel responsible for resting membrane potential...
August 2017: Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/28569901/rates-and-equilibrium-constants-of-the-ligand-induced-conformational-transition-of-an-hcn-ion-channel-protein-domain-determined-by-deer-spectroscopy
#11
Alberto Collauto, Hannah A DeBerg, Royi Kaufmann, William N Zagotta, Stefan Stoll, Daniella Goldfarb
Ligand binding can induce significant conformational changes in proteins. The mechanism of this process couples equilibria associated with the ligand binding event and the conformational change. Here we show that by combining the application of W-band double electron-electron resonance (DEER) spectroscopy with microfluidic rapid freeze quench (μRFQ) it is possible to resolve these processes and obtain both equilibrium constants and reaction rates. We studied the conformational transition of the nitroxide labeled, isolated carboxy-terminal cyclic-nucleotide binding domain (CNBD) of the HCN2 ion channel upon binding of the ligand 3',5'-cyclic adenosine monophosphate (cAMP)...
June 14, 2017: Physical Chemistry Chemical Physics: PCCP
https://www.readbyqxmd.com/read/28528343/the-dome-wall-of-bladder-acts-as-a-pacemaker-site-in-detrusor-instability-in-rats
#12
Qian He, Yan-Lan Yu, Gong-Hui Li, Sheng Chen
BACKGROUND The aim of this study was to confirm that the interstitial cells of Cajal (ICCs) in the dome wall of the bladder are pacemaker cells, and that the dome wall of the bladder acts as a pacemaker site in the detrusor instability (DI) rat model. MATERIAL AND METHODS The model of DI in Wistar rats was established and urodynamic studies measuring the bladder volume and pressure were performed. The detrusor excitability was investigated using the amplitude and frequency of phasic contraction of strips. The localization and quantity of ICCs was identified by immunohistochemistry and c-KIT protein expression in the rat bladder...
May 21, 2017: Medical Science Monitor: International Medical Journal of Experimental and Clinical Research
https://www.readbyqxmd.com/read/28454297/association-between-hyperpolarization-activated-channel-in-interstitial-cells-of-cajal-and-gastrointestinal-dysmotility-induced-by-malignant-ascites
#13
Tieyun Guo, Jiade Li, Jing Li, Dan Kong, Chunli Bi, Zheng He, Dai Tang, Xiaoming Jin, Lianhong Jin
Advanced malignant ascites is accompanied by gastrointestinal dysmotility, and patients often feel abdominal pain, abdominal distention, nausea and constipation. Gastrointestinal dysmotility is not only painful for the patients, but it reduces the absorption of nutrients and affects the physical recovery of patients with malignant ascites. It is reported that changes in interstitial cells of Cajal (ICCs) are responsible for the gastrointestinal dysmotility induced by malignant ascites, but the mechanism is not completely understood...
March 2017: Oncology Letters
https://www.readbyqxmd.com/read/28363781/hyperpolarization-activated-current-ih-in-mouse-trigeminal-sensory-neurons-in-a-transgenic-mouse-model-of-familial-hemiplegic-migraine-type-1
#14
Francesca Eroli, Sandra Vilotti, Arn M J M van den Maagdenberg, Andrea Nistri
Transgenic knock-in (KI) mice that express CaV2.1 channels containing an R192Q gain-of-function mutation in the α1A subunit known to cause familial hemiplegic migraine type-1 in patients, exhibit key disease characteristics and provide a useful tool to investigate pathophysiological mechanisms of pain transduction. Previously, KI trigeminal sensory neurons were shown to exhibit constitutive hyperexcitability due to up-regulation of ATP-gated P2X3 receptors that trigger spike activity at a more negative threshold...
March 29, 2017: Neuroscience
https://www.readbyqxmd.com/read/28296544/the-conduction-system-and-expressions-of-hyperpolarization-activated-cyclic-nucleotide-gated-cation-channel-4-and-connexin43-expressions-in-the-hearts-of-fetal-day-13-mice
#15
Y Wen, B Li
We investigated the development of the sinus node of the heart conduction system by localizing hyperpolarization-activated cyclic nucleotide-gated cation channel 4 (HCN4) and connexin43 (Cx43) in the hearts of fetal day 13 mice. Horizontal serial sections of day 13 whole fetuses were stained by hematoxylin and eosin and immunofluorescence to identify myocardial cells that express HCN4, hyperpolarization-activated cyclic nucleotide-gated cation channel 2 (HCN2) and Cx43. Expression levels of HCN4 and Cx43 were determined by quantitative RT-PCR in both fetal day 13 and adult mice...
2017: Biotechnic & Histochemistry: Official Publication of the Biological Stain Commission
https://www.readbyqxmd.com/read/28252299/multiconfiguration-self-consistent-field-study-on-formonitrile-imine-and-n-substituted-nitrile-imines-hcn2-r-energy-component-analysis-of-the-pseudo-jahn-teller-effect
#16
Azumao Toyota, Takashi Muramatsu, Shiro Koseki
Stable geometrical structures for formonitrile imine (1) and N-substituted nitrile imines HCN2-R (R = Li, BeH, BH2, CH3, CN, CCH, C6H5, NH2, OH, and F) (2-11) were examined by using the multiconfiguration self-consistent-field (MCSCF) method followed by second-order configuration interaction (SOCI) calculations and second-order multiconfiguration quasi-degenerate perturbation theory (MCQDPT2) calculations, together with the aug-cc-pVTZ basis sets. The results show that 1 suffers a pseudo-Jahn-Teller (JT) distortion from a linear C∞v structure to a C1 structure via a planar bent Cs structure...
March 14, 2017: Journal of Physical Chemistry. A
https://www.readbyqxmd.com/read/28219978/a-mutation-in-the-g-protein-gene-gnb2-causes-familial-sinus-node-and-atrioventricular-conduction-dysfunction
#17
Birgit Stallmeyer, Johanna Kuß, Stefan Kotthoff, Sven Zumhagen, Kirsty Vowinkel, Susanne Rinné, Lina A Matschke, Corinna Friedrich, Ellen Schulze-Bahr, Stephan Rust, Guiscard Seebohm, Niels Decher, Eric Schulze-Bahr
RATIONALE: Familial sinus node and atrioventricular conduction dysfunction is a rare disorder that leads to paroxysmal dizziness, fatigue, and syncope because of a temporarily or permanently reduced heart rate. To date, only a few genes for familial sinus and atrioventricular conduction dysfunction are known, and the majority of cases remain pathogenically unresolved. OBJECTIVE: We aim to identify the disease gene in a large 3-generation family (n=25) with autosomal dominant sinus node dysfunction (SND) and atrioventricular block (AVB) and to characterize the mutation-related pathomechanisms in familial SND+AVB...
May 12, 2017: Circulation Research
https://www.readbyqxmd.com/read/28181007/regulation-of-hcn-ion-channels-by-non-canonical-cyclic-nucleotides
#18
REVIEW
Bryan VanSchouwen, Giuseppe Melacini
The hyperpolarization-activated cyclic-nucleotide-modulated (HCN) proteins are cAMP-regulated ion channels that play a key role in nerve impulse transmission and heart rate modulation in neuronal and cardiac cells, respectively. Although they are regulated primarily by cAMP, other cyclic nucleotides such as cGMP, cCMP, and cUMP serve as partial agonists for the HCN2 and HCN4 isoforms. By competing with cAMP for binding, these non-canonical ligands alter ion channel gating, and in turn, modulate the cAMP-dependent activation profiles...
2017: Handbook of Experimental Pharmacology
https://www.readbyqxmd.com/read/28177679/reduced-expression-of-hcn-channels-in-the-sinoatrial-node-of-streptozotocin-induced-diabetic-rats
#19
Xin Huang, Nier Zhong, Hong Zhang, Aiqun Ma, Zuyi Yuan, Ning Guo
Diabetes mellitus (DM) is associated with an electrical remodeling of the heart, increasing the risk of arrhythmias. However, knowledge of electrical remodeling in the sinoatrial node (SAN) by DM is limited. We investigated the expression of HCN channel isoforms, HCN1-HCN4, in SAN from streptozotocin (STZ)-induced diabetic rats and the age-matched controls. We found that the STZ-induced diabetic rats have a lower intrinsic heart rate, a lengthened sinoatrial conduction time, and rate-corrected maximal sinoatrial node recovery time in vivo as well as a longer cycle length (CL) in vitro, as compared with the control...
May 2017: Canadian Journal of Physiology and Pharmacology
https://www.readbyqxmd.com/read/28017718/maturation-and-processing-of-the-amyloid-precursor-protein-is-regulated-by-the-potassium-sodium-hyperpolarization-activated-cyclic-nucleotide-gated-ion-channel-2-hcn2
#20
Susanne Frykman, Mitsuhiro Inoue, Atsushi Ikeda, Yasuhiro Teranishi, Takahiro Kihara, Jolanta L Lundgren, Natsuko G Yamamoto, Nenad Bogdanovic, Bengt Winblad, Sophia Schedin-Weiss, Lars O Tjernberg
The toxic amyloid β-peptide (Aβ) is a key player in Alzheimer Disease (AD) pathogenesis and selective inhibition of the production of this peptide is sought for. Aβ is produced by the sequential cleavage of the Aβ precursor protein (APP) by β-secretase (to yield APP-C-terminal fragment β (APP-CTFβ) and soluble APPβ (sAPPβ)) and γ-secretase (to yield Aβ). We reasoned that proteins that associate with γ-secretase are likely to regulate Aβ production and to be targets of pharmaceutical interventions and therefore performed a pull-down assay to screen for such proteins in rat brain...
January 29, 2017: Biochemical and Biophysical Research Communications
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