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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
#1
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
#2
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
#3
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
#4
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
#5
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
#6
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
#7
Birgit Stallmeyer, Johanna Kuß, Stefan Kotthoff, Sven Zumhagen, Kirsty S Vowinkel, Susanne Rinne, Lina A Matschke, Corinna Friedrich, Ellen Schulze-Bahr, Stephan Rust, Guiscard Seebohm, Niels Decher, Eric Schulze-Bahr
Rationale: Familial sinus node and atrioventricular (AV) conduction dysfunction is a rare disorder that leads to paroxysmal dizziness, fatigue and syncope due to a temporarily or permanent reduced heart rate. To date, only a few genes for familial sinus and/or AV conduction dysfunction are known and the majority of cases remain etiologically unresolved. Objective: We aim to identify the disease gene in a large three-generation family (n=25) with autosomal dominant sinus node dysfunction (SND) and AV block (AVB) and to characterise the mutation-related pathomechanisms in familial SND+AVB...
February 20, 2017: Circulation Research
https://www.readbyqxmd.com/read/28181007/regulation-of-hcn-ion-channels-by-non-canonical-cyclic-nucleotides
#8
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
#9
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
#10
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
https://www.readbyqxmd.com/read/27901476/the-change-of-hcn1-hcn2-mrna-expression-in-peripheral-nerve-after-chronic-constriction-injury-induced-neuropathy-followed-by-pulsed-electromagnetic-field-therapy
#11
Hui Liu, Jun Zhou, Lianbing Gu, Yunxia Zuo
Neuropathic pain is usually defined as a chronic pain state caused by peripheral or central nerve injury as a result of acute damage or systemic diseases. It remains a difficult disease to treat. Recent studies showed that the frequency of action potentials in nociceptive afferents is affected by the activity of hyperpolarization-activated cyclic nucleotide-gated cation channels (HCN) family. In the current study, we used a neuropathy rat model induced by chronic constriction injury (CCI) of sciatic nerve to evaluate the change of expression of HCN1/HCN2 mRNA in peripheral nerve and spinal cord...
January 3, 2017: Oncotarget
https://www.readbyqxmd.com/read/27670841/hyperexcitability-of-mesencephalic-trigeminal-neurons-and-reorganization-of-ion-channel-expression-in-a-rett-syndrome-model
#12
Max F Oginsky, Ningren Cui, Weiwei Zhong, Christopher M Johnson, Chun Jiang
People with Rett syndrome (RTT) have defects in motor function also seen in Mecp2-null mice. Motor function depends on not only central motor commands but also sensory feedback that is vulnerable to changes in excitability of propriosensory neurons. Here we report evidence for hyperexcitability of mesencephalic trigeminal (Me5) neurons in Mecp2-null mice and a novel cellular mechanism for lowering its impact. In in vitro brain slices, the Me5 neurons in both Mecp2(-/Y) male and symptomatic Mecp2(+/-) female mice were overly excitable showing increased firing activity in comparison to their wild-type (WT) male and asymptomatic counterparts...
May 2017: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/27621481/hcn2-ion-channels-basic-science-opens-up-possibilities-for-therapeutic-intervention-in-neuropathic-pain
#13
REVIEW
Christoforos Tsantoulas, Elizabeth R Mooney, Peter A McNaughton
Nociception - the ability to detect painful stimuli - is an invaluable sense that warns against present or imminent damage. In patients with chronic pain, however, this warning signal persists in the absence of any genuine threat and affects all aspects of everyday life. Neuropathic pain, a form of chronic pain caused by damage to sensory nerves themselves, is dishearteningly refractory to drugs that may work in other types of pain and is a major unmet medical need begging for novel analgesics. Hyperpolarisation-activated cyclic nucleotide (HCN)-modulated ion channels are best known for their fundamental pacemaker role in the heart; here, we review data demonstrating that the HCN2 isoform acts in an analogous way as a 'pacemaker for pain', in that its activity in nociceptive neurons is critical for the maintenance of electrical activity and for the sensation of chronic pain in pathological pain states...
September 15, 2016: Biochemical Journal
https://www.readbyqxmd.com/read/27569278/expression-and-cellular-localization-of-hcn-channels-in-rat-cerebellar-granule-neurons
#14
Rafael Zúñiga, Daniela González, Claudio Valenzuela, Nelson Brown, Leandro Zúñiga
Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels belong to the superfamily of voltage-gated pore loop channels. In mammals, this family consists of four different subunits (HCN1-4) and their ion channels activity have been proposed to play an essential role in regulating the membrane potential of excitable cells. Here, we describe the expression and relative abundances of HCN channels in cerebellum and primary cultures of cerebellar granule neurons (CGN). Quantitative determination of mRNA expression levels demonstrated the existence of an accumulation pattern of transcripts in cerebellum that encode HCN2 > HCN3 = HCN4 > HCN1 subunits...
September 23, 2016: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/27568927/cyclic-purine-and-pyrimidine-nucleotides-bind-to-the-hcn2-ion-channel-and-variably-promote-c-terminal-domain-interactions-and-opening
#15
Leo C T Ng, Igor Putrenko, Victoria Baronas, Filip Van Petegem, Eric A Accili
Cyclic AMP is thought to facilitate the opening of the HCN2 channel by binding to a C-terminal domain and promoting or inhibiting interactions between subunits. Here, we correlated the ability of cyclic nucleotides to promote interactions of isolated HCN2 C-terminal domains in solution with their ability to facilitate channel opening. Cyclic IMP, a cyclic purine nucleotide, and cCMP, a cyclic pyrimidine nucleotide, bind to a C-terminal domain containing the cyclic nucleotide-binding domain but, in contrast to other cyclic nucleotides examined, fail to promote its oligomerization, and produce only modest facilitation of opening of the full-length channel...
October 4, 2016: Structure
https://www.readbyqxmd.com/read/27555091/early-cardiac-electrographic-and-molecular-remodeling-in-a-model-of-status-epilepticus-and-acquired-epilepsy
#16
Amy L Brewster, Kyle Marzec, Alexandria Hairston, Marvin Ho, Anne E Anderson, Yi-Chen Lai
OBJECTIVES: A myriad of acute and chronic cardiac alterations are associated with status epilepticus (SE) including increased sympathetic tone, rhythm and ventricular repolarization disturbances. Despite these observations, the molecular processes underlying SE-associated myocardial remodeling remain to be identified. Here we determined early SE-associated myocardial electrical and molecular alterations using a model of SE and acquired epilepsy. METHODS: We performed electrocardiography (ECG) assessments in rats beginning at 2 weeks following kainate-induced SE, and calculated short-term variability (STV) of the corrected QT intervals (QTc) as a marker of ventricular stability...
November 2016: Epilepsia
https://www.readbyqxmd.com/read/27542339/inhibition-of-hcn-channel-activity-in-the-thalamus-attenuates-chronic-pain-in-rats
#17
Weihua Ding, Zerong You, Shiqian Shen, Lucy Chen, Shengmei Zhu, Jianren Mao
Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels regulate neuronal excitability in both peripheral and central nerve systems. Emerging evidence indicates that HCN channels are involved in the development and maintenance of chronic pain. However, the impact of HCN channel activity in the thalamus on chronic pain has not been examined. In this report, we evaluated the effect on nociceptive behaviors after infusion of a HCN channel blocker ZD7288 into the ventral posterolateral (VPL) nucleus of the thalamus in rats with neuropathic pain or monoarthritis...
September 19, 2016: Neuroscience Letters
https://www.readbyqxmd.com/read/27353446/patch-clamp-fluorometry-based-channel-counting-to-determine-hcn-channel-conductance
#18
Chang Liu, Changan Xie, Khade Grant, Zhuocheng Su, Weihua Gao, Qinglian Liu, Lei Zhou
Counting ion channels on cell membranes is of fundamental importance for the study of channel biophysics. Channel counting has thus far been tackled by classical approaches, such as radioactive labeling of ion channels with blockers, gating current measurements, and nonstationary noise analysis. Here, we develop a counting method based on patch-clamp fluorometry (PCF), which enables simultaneous electrical and optical recordings, and apply it to EGFP-tagged, hyperpolarization-activated and cyclic nucleotide-regulated (HCN) channels...
July 2016: Journal of General Physiology
https://www.readbyqxmd.com/read/27347074/expression-of-hyperpolarization-activated-cyclic-nucleotide-gated-channel-isoforms-in-a-canine-model-of-atrial-fibrillation
#19
Wei He, Jian Zhang, Tianyi Gan, Guojun Xu, Baopeng Tang
The aim of the present study was to analyze the mRNA and protein expression levels of atrial hyperpolarization-activated cyclic nucleotide-gated (HCN) channel isoforms in the left atrial muscle of dogs with multiple organ failure. A total of 14 beagle dogs with multiple organ failure, including seven cases with sinus rhythm and seven cases with atrial fibrillation (AF), underwent surgery to remove a sample of left atrial appendage tissue. The expression levels of a number of HCN channel subtypes were subsequently measured using quantitative polymerase chain reaction and western blot analysis...
July 2016: Experimental and Therapeutic Medicine
https://www.readbyqxmd.com/read/27212063/identification-of-methylated-genes-in-salivary-gland-adenoid-cystic-carcinoma-xenografts-using-global-demethylation-and-methylation-microarray-screening
#20
Shizhang Ling, Eleni M Rettig, Marietta Tan, Xiaofei Chang, Zhiming Wang, Mariana Brait, Justin A Bishop, Elana J Fertig, Michael Considine, Michael J Wick, Patrick K Ha
Salivary gland adenoid cystic carcinoma (ACC) is a rare head and neck malignancy without molecular biomarkers that can be used to predict the chemotherapeutic response or prognosis of ACC. The regulation of gene expression of oncogenes and tumor suppressor genes (TSGs) through DNA promoter methylation may play a role in the carcinogenesis of ACC. To identify differentially methylated genes in ACC, a global demethylating agent, 5-aza-2'-deoxycytidine (5-AZA) was utilized to unmask putative TSG silencing in ACC xenograft models in mice...
July 2016: International Journal of Oncology
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