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https://www.readbyqxmd.com/read/29565972/activation-gating-in-hcn2-channels
#1
Sabine Hummert, Susanne Thon, Thomas Eick, Ralf Schmauder, Eckhard Schulz, Klaus Benndorf
Hyperpolarization-activated cyclic nucleotide-modulated (HCN) channels control electrical rhythmicity in specialized brain and heart cells. We quantitatively analysed voltage-dependent activation of homotetrameric HCN2 channels and its modulation by the second messenger cAMP using global fits of hidden Markovian models to complex experimental data. We show that voltage-dependent activation is essentially governed by two separable voltage-dependent steps followed by voltage-independent opening of the pore. According to this model analysis, the binding of cAMP to the channels exerts multiple effects on the voltage-dependent gating: It stabilizes the open pore, reduces the total gating charge from ~8 to ~5, makes an additional closed state outside the activation pathway accessible and strongly accelerates the ON-gating but not the OFF-gating...
March 2018: PLoS Computational Biology
https://www.readbyqxmd.com/read/29519998/hcn2-rescues-brain-defects-by-enforcing-endogenous-voltage-pre-patterns
#2
Vaibhav P Pai, Alexis Pietak, Valerie Willocq, Bin Ye, Nian-Qing Shi, Michael Levin
Endogenous bioelectrical signaling coordinates cell behaviors toward correct anatomical outcomes. Lack of a model explaining spatialized dynamics of bioelectric states has hindered the understanding of the etiology of some birth defects and the development of predictive interventions. Nicotine, a known neuroteratogen, induces serious defects in brain patterning and learning. Our bio-realistic computational model explains nicotine's effects via the disruption of endogenous bioelectrical gradients and predicts that exogenous HCN2 ion channels would restore the endogenous bioelectric prepatterns necessary for brain patterning...
March 8, 2018: Nature Communications
https://www.readbyqxmd.com/read/29466436/loss-of-hcn2-leads-to-delayed-gastrointestinal-motility-and-reduced-energy-intake-in-mice
#3
Daniel W Fisher, Phillip Luu, Neha Agarwal, Jonathan E Kurz, Dane M Chetkovich
Hyperpolarization-activated Cyclic Nucleotide-gated (HCN) channels are important regulators of excitability in neural, cardiac, and other pacemaking cells, which are often altered in disease. In mice, loss of HCN2 leads to cardiac dysrhythmias, persistent spike-wave discharges similar to those seen in absence epilepsy, ataxia, tremor, reduced neuropathic and inflammatory pain, antidepressant-like behavior, infertility, and severely restricted growth. While many of these phenotypes have tissue-specific mechanisms, the cause of restricted growth in HCN2 knockout animals remains unknown...
2018: PloS One
https://www.readbyqxmd.com/read/29401592/kir2-inward-rectification-controlled-precise-and-dynamic-balances-between-kir2-and-hcn-currents-initiate-pacemaking-activity
#4
Kuihao Chen, Dongchuan Zuo, Sho-Ya Wang, Haijun Chen
Spontaneous rhythmic action potential or pacemaking activity of pacemaker cells controls rhythmic signaling such as heartbeat. The mechanism underlying the origin of pacemaking activity is not well understood. In this study, we created human embryonic kidney (HEK) 293 cells that show pacemaking activity through heterologous expression of strong inward rectifier K+ channels (Kir2.1), hyperpolarization-activated cyclic nucleotide-gated nonselective cation channels (HCN2), and voltage-gated Na+ or Ca2+ channels (Nav1...
January 12, 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/29394509/increase-of-hcn-current-in-the-aberrant-excitability-of-spinal-muscular-atrophy
#5
Hsing-Jung Lai, Chien-Lin Chen, Li-Kai Tsai
Objective The pathophysiology of spinal muscular atrophy (SMA) is still unclear. Methods The nerve excitability test in SMA patients and a mouse model of SMA was carried out to explore the pathophysiology of nodal and internodal currents, and quantitative PCR, Western blotting and whole-cell patch-clamp recording were used for the identified hypothesis. Results The nerve excitability test in SMA patients showed increased inward rectification in the current-threshold relationship and increased overshoot after hyperpolarizing threshold electrotonus, which indicates increased hyperpolarization-activated cyclic nucleotide-gated (HCN) current; these findings correlated with disease severity...
February 2, 2018: Annals of Neurology
https://www.readbyqxmd.com/read/29366880/increased-hcn-channel-activity-in-the-gasserian-ganglion-contributes-to-trigeminal-neuropathic-pain
#6
Weihua Ding, Zerong You, Shiqian Shen, Jinsheng Yang, Grewo Lim, Jason T Doheny, Shengmei Zhu, Yi Zhang, Lucy Chen, Jianren Mao
Orofacial neuropathic pain caused by trigeminal nerve injury is a debilitating condition with limited therapeutic options. Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels regulate neuronal excitability and are involved in the development and maintenance of chronic pain. However, the effect of HCN channel activity in the Gasserian ganglion on trigeminal neuropathic pain has not been examined. We evaluated nociceptive behaviors after microinjection of the HCN channel blockers ZD7288 or ivabradine into the Gasserian ganglion in rats with trigeminal nerve injury...
January 31, 2018: Journal of Pain: Official Journal of the American Pain Society
https://www.readbyqxmd.com/read/29339292/selective-hcn1-block-as-a-strategy-to-control-oxaliplatin-induced-neuropathy
#7
F Resta, L Micheli, A Laurino, V Spinelli, T Mello, L Sartiani, L Di Cesare Mannelli, E Cerbai, C Ghelardini, M N Romanelli, G Mannaioni, A Masi
Chemotherapy-Induced Peripheral Neuropathy (CIPN) is the most frequent adverse effect of pharmacological cancer treatments. The occurrence of neuropathy prevents the administration of fully-effective drug regimen, affects negatively the quality of life of patients, and may lead to therapy discontinuation. CIPN is currently treated with anticonvulsants, antidepressants, opioids and non-opioid analgesics, all of which are flawed by insufficient anti-hyperalgesic efficacy or addictive potential. Understandably, developing new drugs targeting CIPN-specific pathogenic mechanisms would dramatically improve efficacy and tolerability of anti-neuropathic therapies...
March 15, 2018: Neuropharmacology
https://www.readbyqxmd.com/read/29327340/shank3-deficient-thalamocortical-neurons-show-hcn-channelopathy-and-alterations-in-intrinsic-electrical-properties
#8
Mengye Zhu, Vinay Kumar Idikuda, Jianbing Wang, Fusheng Wei, Virang Kumar, Nikhil Shah, Christopher B Waite, Qinglian Liu, Lei Zhou
KEY POINTS: Shank3 increases the HCN channel surface expression in heterologous expression systems. Shank3Δ13-16 deficiency causes significant reduction in HCN2 expression and Ih current amplitude in thalamocortical (TC) neurons. Shank3Δ13-16 - but not Shank3Δ4-9 -deficient TC neurons share changes in basic electrical properties which are comparable to those of HCN2-/- TC neurons. HCN channelopathy may critically mediate events downstream from Shank3 deficiency. ABSTRACT: SHANK3 is a scaffolding protein that is highly enriched in excitatory synapses...
April 1, 2018: Journal of Physiology
https://www.readbyqxmd.com/read/29282531/kir2-1-channels-set-two-levels-of-resting-membrane-potential-with-inward-rectification
#9
Kuihao Chen, Dongchuan Zuo, Zheng Liu, Haijun Chen
Strong inward rectifier K+ channels (Kir2.1) mediate background K+ currents primarily responsible for maintenance of resting membrane potential. Multiple types of cells exhibit two levels of resting membrane potential. Kir2.1 and K2P1 currents counterbalance, partially accounting for the phenomenon of human cardiomyocytes in subphysiological extracellular K+ concentrations or pathological hypokalemic conditions. The mechanism of how Kir2.1 channels contribute to the two levels of resting membrane potential in different types of cells is not well understood...
April 2018: Pflügers Archiv: European Journal of Physiology
https://www.readbyqxmd.com/read/29064616/gain-of-function-hcn2-variants-in-genetic-epilepsy
#10
Melody Li, Snezana Maljevic, A Marie Phillips, Slave Petrovski, Michael S Hildebrand, Rosemary Burgess, Therese Mount, Federico Zara, Pasquale Striano, Julian Schubert, Holger Thiele, Peter Nürnberg, Michael Wong, Judith L Weisenberg, Liu Lin Thio, Holger Lerche, Ingrid E Scheffer, Samuel F Berkovic, Steven Petrou, Christopher A Reid
Genetic generalized epilepsy (GGE) is a common epilepsy syndrome that encompasses seizure disorders characterized by spike-and-wave discharges (SWDs). Pacemaker hyperpolarization-activated cyclic nucleotide-gated channels (HCN) are considered integral to SWD genesis, making them an ideal gene candidate for GGE. We identified HCN2 missense variants from a large cohort of 585 GGE patients, recruited by the Epilepsy Phenome-Genome Project (EPGP), and performed functional analysis using two-electrode voltage clamp recordings from Xenopus oocytes...
February 2018: Human Mutation
https://www.readbyqxmd.com/read/29054409/dual-expression-of-constitutively-active-g%C3%AE-s-protein-coupled-receptors-differentially-establishes-the-resting-activity-of-the-camp-gated-hcn2-channel-in-a-single-compartment
#11
Noriyuki Nakashima, Kie Nakashima, Takeo Nakayama, Akiko Takaku, Ryosuke Kanamori
The hyperpolarization-activated cyclic nucleotide-gated 2 (HCN2) channel is a major subtype of the HCN channel family expressed in the nervous system that sets the membrane potential, regulates cell excitability and senses changes in the extracellular environment. Neurons express various Gαs -protein-coupled receptors (GPCRs), many of which show ligand-independent constitutive activity. These membrane-bound proteins are expressed in various subcellular compartments of neurons. Therefore, some proportion of HCN2 channels opens in response to the basal cAMP pool size produced by constitutively active GPCRs...
December 9, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29047147/case-control-pharmacogenetic-study-of-hcn1-hcn2-variants-and-genetic-generalized-epilepsies
#12
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)...
March 2018: 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
#13
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
#14
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
#15
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
#16
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
#17
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. In addition to binding to the carboxyl-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...
October 27, 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
#18
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
#19
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
#20
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
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