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https://www.readbyqxmd.com/read/29163060/nmda-receptors-regulate-the-development-of-neuronal-intrinsic-excitability-through-cell-autonomous-mechanisms
#1
Guoqiang Hou, Zhong-Wei Zhang
Maturation of neuronal and synaptic functions during early life is essential for the development of neuronal circuits and behaviors. In newborns synaptic transmission at excitatory synapses is primarily mediated by N-methyl-D-aspartate receptors (NMDARs), and NMDAR-mediated signaling plays an important role in synaptic maturation. Concomitant with synapse development, the intrinsic properties of neurons undergo dramatic changes during early life. However, little is known about the role of NMDARs in the development of intrinsic excitability...
2017: Frontiers in Cellular Neuroscience
https://www.readbyqxmd.com/read/29094305/noradrenergic-fiber-sprouting-and-altered-transduction-in-neuropathic-prefrontal-cortex
#2
Steven Cordeiro Matos, Maria Zamfir, Geraldine Longo, Alfredo Ribeiro-da-Silva, Philippe Séguéla
Functional changes in hyperpolarization-activated and cyclic nucleotide-gated (HCN) channels have been shown to contribute to medial prefrontal (mPFC) hyperexcitability after peripheral nerve injury. A reduction in the open probability of these neuronal channels might be relevant since this can enhance membrane input resistance and synaptic summation. However, the molecular mechanisms underlying neuropathy-associated alterations in HCN channel activity remain elusive. Using the spared nerve injury model of neuropathic pain in Long-Evans rats, we first discovered a significant increase in noradrenergic innervation within the mPFC of nerve-injured compared to control animals...
November 1, 2017: Brain Structure & Function
https://www.readbyqxmd.com/read/29064616/gain-of-function-hcn2-variants-in-genetic-epilepsy
#3
Melody Li, Snezana Maljevic, A Marie Phillips, Slave Petrovski, Michael 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...
October 24, 2017: 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
#4
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/28973319/differential-effects-of-hcn-channel-block-on-on-and-off-pathways-in-the-retina-as-a-potential-cause-for-medication-induced-phosphene-perception
#5
Sebastian Bemme, Michael Weick, Tim Gollisch
Purpose: Phosphene perception is a characteristic side effect of heart rate-reducing medication that acts on hyperpolarization-activated cyclic nucleotide-gated (HCN) ion channels. It is hypothesized that these phosphenes are caused by blocking HCN channels in photoreceptors and neurons of the retina, yet the underlying changes in visual signal processing in the retina caused by the HCN channel block are still unknown. Methods: We examined the effects of pharmacologic HCN channel block on the encoding of visual signals in retinal ganglion cells by recording ganglion cell spiking activity from isolated mouse retinas mounted on multielectrode arrays...
September 1, 2017: Investigative Ophthalmology & Visual Science
https://www.readbyqxmd.com/read/28957668/aldosterone-sensing-neurons-in-the-nts-exhibit-state-dependent-pacemaker-activity-and-drive-sodium-appetite-via-synergy-with-angiotensin-ii-signaling
#6
Jon M Resch, Henning Fenselau, Joseph C Madara, Chen Wu, John N Campbell, Anna Lyubetskaya, Brian A Dawes, Linus T Tsai, Monica M Li, Yoav Livneh, Qingen Ke, Peter M Kang, Géza Fejes-Tóth, Anikó Náray-Fejes-Tóth, Joel C Geerling, Bradford B Lowell
Sodium deficiency increases angiotensin II (ATII) and aldosterone, which synergistically stimulate sodium retention and consumption. Recently, ATII-responsive neurons in the subfornical organ (SFO) and aldosterone-sensitive neurons in the nucleus of the solitary tract (NTS(HSD2) neurons) were shown to drive sodium appetite. Here we investigate the basis for NTS(HSD2) neuron activation, identify the circuit by which NTS(HSD2) neurons drive appetite, and uncover an interaction between the NTS(HSD2) circuit and ATII signaling...
September 27, 2017: Neuron
https://www.readbyqxmd.com/read/28950029/investigating-cyclic-nucleotide-and-cyclic-dinucleotide-binding-to-hcn-channels-by-surface-plasmon-resonance
#7
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/28928053/development-of-correction-formula-for-field-potential-duration-of-human-induced-pluripotent-stem-cell-derived-cardiomyocytes-sheets
#8
Hiroko Izumi-Nakaseko, Yasunari Kanda, Yuji Nakamura, Mihoko Hagiwara-Nagasawa, Takeshi Wada, Kentaro Ando, Atsuhiko T Naito, Yuko Sekino, Atsushi Sugiyama
Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have been used in many studies to assess proarrhythmic risks of chemical compounds. In those studies, field potential durations (FPD) of hiPSC-CMs have been corrected by clinically used Fridericia's and/or Bazett's formulae, however, the rationale for the use of these formulae has not been well established. In the present study, we developed a correction formula for experiments using hiPSC-CMs. First, we analyzed the effect of beating rate on FPD in the hiPSC-CMs sheets with electrical stimuli and a HCN channel inhibitor zatebradine...
September 6, 2017: Journal of Pharmacological Sciences
https://www.readbyqxmd.com/read/28904107/hyperpolarization-activated-cyclic-nucleotide-gated-channels-potentially-modulate-axonal-excitability-at-different-thresholds
#9
Dinushi Weerasinghe, Parvathi Menon, Steve Vucic
Hyperpolarization-activated cyclic-nucleotide gated (HCN) channels mediate differences in sensory and motor axonal excitability at different thresholds in animal models. Importantly, HCN channels are responsible for voltage-gated inward rectifying (Ih) currents activated during hyperpolarization. The Ih currents exert a crucial role in determining the resting membrane potential and have been implicated in a variety of neurological disorders, including neuropathic pain. In humans, differences in biophysical properties of motor and sensory axons at different thresholds remain to be elucidated and could provide crucial pathophysiological insights in peripheral neurological diseases...
September 13, 2017: Journal of Neurophysiology
https://www.readbyqxmd.com/read/28887304/allostery-between-two-binding-sites-in-the-ion-channel-subunit-trip8b-confers-binding-specificity-to-hcn-channels
#10
Kyle A Lyman, Ye Han, Robert J Heuermann, Xiangying Cheng, Jonathan E Kurz, Reagan E Lyman, Paul P Van Veldhoven, Dane M Chetkovich
Tetratricopeptide repeat (TPR) domains are ubiquitous structural motifs that mediate protein-protein interactions. For example, the TPR domains in the peroxisomal import receptor PEX5 enable binding to a range of type 1 peroxisomal targeting signal motifs. A homolog of PEX5, tetratricopeptide repeat-containing Rab8b-interacting protein (TRIP8b), binds to and functions as an auxiliary subunit of hyperpolarization-activated cyclic nucleotide (HCN)-gated channels. Given the similarity between TRIP8b and PEX5, this difference in function raises the question of what mechanism accounts for their binding specificity...
October 27, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28878030/the-hyperpolarization-activated-cyclic-nucleotide-gated-channels-from-biophysics-to-pharmacology-of-a-unique-family-of-ion-channels
#11
REVIEW
Laura Sartiani, Guido Mannaioni, Alessio Masi, Maria Novella Romanelli, Elisabetta Cerbai
Hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels are important members of the voltage-gated pore loop channels family. They show unique features: they open at hyperpolarizing potential, carry a mixed Na/K current, and are regulated by cyclic nucleotides. Four different isoforms have been cloned (HCN1-4) that can assemble to form homo- or heterotetramers, characterized by different biophysical properties. These proteins are widely distributed throughout the body and involved in different physiologic processes, the most important being the generation of spontaneous electrical activity in the heart and the regulation of synaptic transmission in the brain...
October 2017: Pharmacological Reviews
https://www.readbyqxmd.com/read/28877547/comparing-excitability-at-37%C3%A2-c-versus-at-20%C3%A2-c-differences-between-motor-and-sensory-axons
#12
Maria O Kovalchuk, Hessel Franssen, Leonard J Van Schelven, Boudewijn T H M Sleutjes
INTRODUCTION: In some peripheral nervous system disorders, cold induces symptoms of muscle weakness without loss of sensation. To understand this selective effect on motor function, it is first essential to delineate the effects of cooling in motor and sensory axons of healthy subjects. METHODS: In 17 healthy volunteers, we performed excitability and clinical tests of median nerve motor and sensory axons at 37°C and at 20°C. Clinical tests consisted of assessing thenar muscle strength, 2-point discrimination, and joint position sense of the third finger...
September 6, 2017: Muscle & Nerve
https://www.readbyqxmd.com/read/28871229/gabapentin-modulates-hcn4-channel-voltage-dependence
#13
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/28868308/phosphodiesterases-3-and-4-differentially-regulate-the-funny-current-if-in-mouse-sinoatrial-node-myocytes
#14
Joshua R St Clair, Eric D Larson, Emily J Sharpe, Zhandi Liao, Catherine Proenza
Cardiac pacemaking, at rest and during the sympathetic fight-or-flight response, depends on cAMP (3',5'-cyclic adenosine monophosphate) signaling in sinoatrial node myocytes (SAMs). The cardiac "funny current" (If) is among the cAMP-sensitive effectors that drive pacemaking in SAMs. If is produced by hyperpolarization-activated, cyclic nucleotide-sensitive (HCN) channels. Voltage-dependent gating of HCN channels is potentiated by cAMP, which acts either by binding directly to the channels or by activating the cAMP-dependent protein kinase (PKA), which phosphorylates them...
September 2017: Journal of Cardiovascular Development and Disease
https://www.readbyqxmd.com/read/28864772/mechanism-for-the-inhibition-of-the-camp-dependence-of-hcn-ion-channels-by-the-auxiliary-subunit-trip8b
#15
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/28855177/small-functional-if-current-in-sinoatrial-pacemaker-cells-of-the-brown-trout-salmo-trutta-fario-heart-despite-strong-expression-of-hcn-channel-transcripts
#16
Minna Hassinen, Jaakko Haverinen, Matti Vornanen
Funny current (If), formed by hyperpolarization-activated HCN channels, is supposed to be crucial for membrane clock regulating the cardiac pacemaker mechanism. We examined the presence and activity of HCN channels in the brown trout (Salmo trutta fario) sinoatrial (SA) pacemaker cells, and their putative role in heart rate (fH) regulation. Six HCN transcripts (HCN1, HCN2a, HCN2ba, HCN2bb, HCN3 and HCN4) were expressed in the brown trout heart. The total HCN transcript abundance was 4.0 and 4.9 times higher in SA pacemaker tissue than in atrium and ventricle, respectively...
August 30, 2017: American Journal of Physiology. Regulatory, Integrative and Comparative Physiology
https://www.readbyqxmd.com/read/28844644/role-of-corticotropin-releasing-factor-in-cerebellar-motor-control-and-ataxia
#17
Yi Wang, Zhang-Peng Chen, Qian-Xing Zhuang, Xiao-Yang Zhang, Hong-Zhao Li, Jian-Jun Wang, Jing-Ning Zhu
Cerebellar ataxia, characterized by motor incoordination, postural instability, and gait abnormality [1-3], greatly affects daily activities and quality of life. Although accumulating genetic and non-genetic etiological factors have been revealed [4-7], effective therapies for cerebellar ataxia are still lacking. Intriguingly, corticotropin-releasing factor (CRF), a peptide hormone and neurotransmitter [8, 9], is considered a putative neurotransmitter in the olivo-cerebellar system [10-14]. Notably, decreased levels of CRF in the inferior olive (IO), the sole origin of cerebellar climbing fibers, have been reported in patients with spinocerebellar degeneration or olivopontocerebellar atrophy [15, 16], yet little is known about the exact role of CRF in cerebellar motor coordination and ataxia...
September 11, 2017: Current Biology: CB
https://www.readbyqxmd.com/read/28842863/an-analysis-of-waves-underlying-grid-cell-firing-in-the-medial-enthorinal-cortex
#18
Mayte Bonilla-Quintana, Kyle C A Wedgwood, Reuben D O'Dea, Stephen Coombes
Layer II stellate cells in the medial enthorinal cortex (MEC) express hyperpolarisation-activated cyclic-nucleotide-gated (HCN) channels that allow for rebound spiking via an [Formula: see text] current in response to hyperpolarising synaptic input. A computational modelling study by Hasselmo (Philos. Trans. R. Soc. Lond. B, Biol. Sci. 369:20120523, 2013) showed that an inhibitory network of such cells can support periodic travelling waves with a period that is controlled by the dynamics of the [Formula: see text] current...
August 25, 2017: Journal of Mathematical Neuroscience
https://www.readbyqxmd.com/read/28821541/targeting-mir-423-5p-reverses-exercise-training-induced-hcn4-channel-remodeling-and-sinus-bradycardia
#19
Alicia D'Souza, Charles M Pearman, Yanwen Wang, Shu Nakao, Sunil Jit R J Logantha, Charlotte Cox, Hayley Bennett, Yu Zhang, Anne Berit Johnsen, Nora Linscheid, Pi Camilla Poulsen, Jonathan Elliott, Jessica Coulson, Jamie McPhee, Abigail Robertson, Paula A da Costa Martins, Ashraf Kitmitto, Ulrik Wisløff, Elizabeth J Cartwright, Oliver Monfredi, Alicia Lundby, Halina Dobrzynski, Delvac Oceandy, Gwilym M Morris, Mark R Boyett
RATIONALE: Downregulation of the pacemaking ion channel, HCN4 (hyperpolarization-activated cyclic nucleotide gated channel 4), and the corresponding ionic current, If, underlies exercise training-induced sinus bradycardia in rodents. If this occurs in humans, it could explain the increased incidence of bradyarrhythmias in veteran athletes, and it will be important to understand the underlying processes. OBJECTIVE: To test the role of HCN4 in the training-induced bradycardia in human athletes and investigate the role of microRNAs (miRs) in the repression of HCN4...
October 13, 2017: Circulation Research
https://www.readbyqxmd.com/read/28818840/hcn4-ion-channel-function-is-required-for-early-events-that-regulate-anatomical-left-right-patterning-in-a-nodal-and-lefty-asymmetric-gene-expression-independent-manner
#20
Vaibhav P Pai, Valerie Willocq, Emily J Pitcairn, Joan M Lemire, Jean-François Paré, Nian-Qing Shi, Kelly A McLaughlin, Michael Levin
Laterality is a basic characteristic of all life forms, from single cell organisms to complex plants and animals. For many metazoans, consistent left-right asymmetric patterning is essential for the correct anatomy of internal organs, such as the heart, gut, and brain; disruption of left-right asymmetry patterning leads to an important class of birth defects in human patients. Laterality functions across multiple scales, where early embryonic, subcellular and chiral cytoskeletal events are coupled with asymmetric amplification mechanisms and gene regulatory networks leading to asymmetric physical forces that ultimately result in distinct left and right anatomical organ patterning...
October 15, 2017: Biology Open
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