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https://www.readbyqxmd.com/read/28219978/a-mutation-in-the-g-protein-gene-gnb2-causes-familial-sinus-node-and-atrioventricular-conduction-dysfunction
#1
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
#2
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...
February 9, 2017: Handbook of Experimental Pharmacology
https://www.readbyqxmd.com/read/28177679/reduced-expression-of-hcn-channels-in-sinoatrial-node-of-streptozotocin-induced-diabetic-rats
#3
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 risk of arrhythmias. However, knowledge of electrical remodeling in 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...
December 23, 2016: 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
#4
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
#5
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
#6
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
#7
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
#8
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
#9
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
#10
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
#11
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
#12
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
#13
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
#14
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
https://www.readbyqxmd.com/read/27137910/relevance-of-hcn2-expressing-human-mesenchymal-stem-cells-for-the-generation-of-biological-pacemakers
#15
Ieva Bruzauskaite, Daiva Bironaite, Edvardas Bagdonas, Vytenis Arvydas Skeberdis, Jaroslav Denkovskij, Tomas Tamulevicius, Valentinas Uvarovas, Eiva Bernotiene
BACKGROUND: The transfection of human mesenchymal stem cells (hMSCs) with the hyperpolarization-activated cyclic nucleotide-gated ion channel 2 (HCN2) gene has been demonstrated to provide biological pacing in dogs with complete heart block. The mechanism appears to be the generation of the ion current (If) by the HCN2-expressing hMSCs. However, it is not clear how the transfection process and/or the HCN2 gene affect the growth functions of the hMSCs. Therefore, we investigated survival, proliferation, cell cycle, and growth on a Kapton® scaffold of HCN2-expressing hMSCs...
April 30, 2016: Stem Cell Research & Therapy
https://www.readbyqxmd.com/read/27131920/kynurenic-acid-and-zaprinast-induce-analgesia-by-modulating-hcn-channels-through-gpr35-activation
#16
Francesco Resta, Alessio Masi, Maria Sili, Annunziatina Laurino, Flavio Moroni, Guido Mannaioni
Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels have a key role in the control of cellular excitability. HCN2, a subgroup of the HCN family channels, are heavily expressed in small dorsal root ganglia (DRG) neurons and their activation seems to be important in the determination of pain intensity. Intracellular elevation of cAMP levels activates HCN-mediated current (Ih) and small DRG neurons excitability. GPR35, a Gi/o coupled receptor, is highly expressed in small DRG neurons, and we hypothesized that its activation, mediated by endogenous or exogenous ligands, could lead to pain control trough a reduction of Ih current...
September 2016: Neuropharmacology
https://www.readbyqxmd.com/read/27085590/baclofen-ameliorates-spatial-working-memory-impairments-induced-by-chronic-cerebral-hypoperfusion-via-up-regulation-of-hcn2-expression-in-the-pfc-in-rats
#17
Pan Luo, Cheng Chen, Yun Lu, TianLi Fu, Qing Lu, Xulin Xu, Changjun Li, Zhi He, Lianjun Guo
Chronic cerebral hypoperfusion (CCH) causes memory deficits and increases the risk of vascular dementia (VD) through several biologically plausible pathways. However, whether CCH causes prefrontal cortex (PFC)-dependent spatial working memory impairments and Baclofen, a GABAB receptor agonist, could ameliorate the impairments is still not clear especially the mechanisms underlying the process. In this study, rats were subjected to permanent bilateral occlusion of the common carotid arteries (two-vessel occlusion, 2VO) to induce CCH...
July 15, 2016: Behavioural Brain Research
https://www.readbyqxmd.com/read/27047338/reduced-hyperpolarization-activated-current-contributes-to-enhanced-intrinsic-excitability-in-cultured-hippocampal-neurons-from-prp-mice
#18
Jing Fan, Patrick L Stemkowski, Maria A Gandini, Stefanie A Black, Zizhen Zhang, Ivana A Souza, Lina Chen, Gerald W Zamponi
Genetic ablation of cellular prion protein (PrP(C)) has been linked to increased neuronal excitability and synaptic activity in the hippocampus. We have previously shown that synaptic activity in hippocampi of PrP-null mice is increased due to enhanced N-methyl-D-aspartate receptor (NMDAR) function. Here, we focused on the effect of PRNP gene knock-out (KO) on intrinsic neuronal excitability, and in particular, the underlying ionic mechanism in hippocampal neurons cultured from P0 mouse pups. We found that the absence of PrP(C) profoundly affected the firing properties of cultured hippocampal neurons in the presence of synaptic blockers...
2016: Frontiers in Cellular Neuroscience
https://www.readbyqxmd.com/read/27047336/involvement-of-hcn-channel-in-muscarinic-inhibitory-action-on-tonic-firing-of-dorsolateral-striatal-cholinergic-interneurons
#19
Zhe Zhao, Kang Zhang, Xiaoyan Liu, Haitao Yan, Xiaoyun Ma, Shuzhuo Zhang, Jianquan Zheng, Liyun Wang, Xiaoli Wei
The striatum is the most prominent nucleus in the basal ganglia and plays an important role in motor movement regulation. The cholinergic interneurons (ChIs) in striatum are involved in the motion regulation by releasing acetylcholine (ACh) and modulating the output of striatal projection neurons. Here, we report that muscarinic ACh receptor (M receptor) agonists, ACh and Oxotremorine (OXO-M), decreased the firing frequency of ChIs by blocking the hyperpolarization-activated cyclic nucleotide-gated (HCN) channels...
2016: Frontiers in Cellular Neuroscience
https://www.readbyqxmd.com/read/26636938/conformational-flip-of-nonactivated-hcn2-channel-subunits-evoked-by-cyclic-nucleotides
#20
Susanne Thon, Eckhard Schulz, Jana Kusch, Klaus Benndorf
Hyperpolarization-activated cyclic nucleotide-modulated (HCN) channels are tetrameric proteins that evoke electrical rhythmicity in specialized neurons and cardiomyocytes. The channels are activated by hyperpolarizing voltage but are also receptors for the intracellular ligand adenosine-3',5'-cyclic monophosphate (cAMP) that enhances activation but is unable to activate the channels alone. Using fcAMP, a fluorescent derivative of cAMP, we analyzed the effect of ligand binding on HCN2 channels not preactivated by voltage...
December 1, 2015: Biophysical Journal
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