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https://www.readbyqxmd.com/read/28904107/hyperpolarization-activated-cyclic-nucleotide-gated-channels-potentially-modulate-axonal-excitability-at-different-thresholds
#1
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
#2
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 (PTS1) 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-gated (HCN) channels. Given the similarity between TRIP8b and PEX5, this difference in function raises the question of what mechanism accounts for their binding specificity...
September 8, 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
#3
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-with-20%C3%A2-c-differences-between-motor-and-sensory-axons
#4
Maria O Kovalchuk, Hessel Franssen, Leonard 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 necessary 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 20°C. Clinical tests consisted of assessing thenar muscle strength, 2-point discrimination and joint position sense of the 3(rd) finger...
September 6, 2017: Muscle & Nerve
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/28868308/phosphodiesterases-3-and-4-differentially-regulate-the-funny-current-if-in-mouse-sinoatrial-node-myocytes
#6
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
#7
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/28855177/small-functional-if-current-in-sinoatrial-pacemaker-cells-of-the-brown-trout-salmo-trutta-fario-heart-despite-strong-expression-of-hcn-channel-transcripts
#8
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
#9
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
#10
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
#11
Alicia D'Souza, Charles M Pearman, Yanwen Wang, Shu Nakao, Sunil Jit R Logantha, Charlotte Cox, Hayley J Bennett, Yu Zhang, Anne Berit Johnsen, Nora Linscheid, Pi C Poulsen, Jonathan Elliott, Jessica Coulson, Jamie S McPhee, Abigail C Robertson, Paula A da Costa Martins, Ashraf Kitmitto, Ulrik Wisloff, 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, 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 micro-RNAs (miRs) in the repression of HCN4. Methods and Results: As in rodents, the intrinsic heart rate was significantly lower in human athletes than non-athletes and in all subjects the rate-lowering effect of the HCN selective blocker, ivabradine, was significantly correlated with the intrinsic heart rate, consistent with HCN repression in athletes...
August 17, 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
#12
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...
August 17, 2017: Biology Open
https://www.readbyqxmd.com/read/28782641/nitric-oxide-cgmp-signaling-via-guanylyl-cyclase-isoform-1-modulates-glutamate-and-gaba-release-in-somatosensory-cortex-of-mice
#13
Qi Wang, Evanthia Mergia, Doris Koesling, Thomas Mittmann
In hippocampus, two guanylyl cyclases (NO-GC1 and NO-GC2) are involved in the transduction of the effects of nitric oxide (NO) on synaptic transmission. However, the respective roles of the NO-GC isoforms on synaptic transmission are less clear in other regions of the brain. In the present study, we used knock-out mice deficient for the NO-GC1 isoform (NO-GC1 KO) to analyze its role in the glutamatergic and GABAergic neurotransmission at pyramidal neurons in layers II/III of somatosensory cortex. NO-GC1 KO slices revealed reduced frequencies of miniature excitatory- and inhibitory-postsynaptic currents, increased paired-pulse ratios and decreased input-output curves of evoked signals, which indicated the reduction of glutamate and GABA release in NO-GC1 KO mice...
August 4, 2017: Neuroscience
https://www.readbyqxmd.com/read/28768741/theta-frequency-selectivity-in-the-somatic-spike-triggered-average-of-rat-hippocampal-pyramidal-neurons-is-dependent-on-hcn-channels
#14
Anindita Das, Rishikesh Narayanan
The ability to distill specific frequencies from complex spatiotemporal patterns of afferent inputs is a pivotal functional requirement for neurons residing in networks receiving frequency-multiplexed inputs. Although the expression of theta-frequency subthreshold resonance is established in hippocampal pyramidal neurons, it is not known if their spike initiation dynamics manifest spectral selectivity or if their intrinsic properties are tuned to process gamma-frequency inputs. Here, we measured the spike-triggered average (STA) of rat hippocampal pyramidal neurons through electrophysiological recordings and quantified spectral selectivity in their spike initiation dynamics and their coincidence detection window (CDW)...
August 2, 2017: Journal of Neurophysiology
https://www.readbyqxmd.com/read/28762726/intracellular-uncaging-of-cgmp-with-blue-light
#15
Hitesh K Agarwal, Shenyu Zhai, D James Surmeier, Graham C R Ellis-Davies
We have made a new caged cGMP that is photolyzed with blue light. Using our recently developed derivative of 7-diethylaminocourmarin (DEAC) called DEAC450, we synthesized coumarin phosphoester derivatives of cGMP with two negative charges appended to the DEAC450 moiety. DEAC450-cGMP is freely soluble in physiological buffer without the need for any organic cosolvents. With a photolysis quantum yield of 0.18 and an extinction coefficient of 43 000 M(-1) cm(-1) at 453 nm, DEAC450-cGMP is the most photosensitive caged cGMP made to date...
August 1, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28746826/electrophysiological-properties-of-neurons-and-synapses-in-the-lateral-habenular-complex-lhb
#16
REVIEW
Franziska Wagner, Torsten Weiss, Rüdiger W Veh
Animal including human behavior is highly sophisticated. Besides reflective actions it is largely based on the desire for magnificent internal feelings, which are provided by the reward system. Its counterpart an "anti-reward" system is mainly composed of the lateral habenular complex (LHb) and its extensive interconnections with the monoaminergic cell groups in the mid- and hindbrain. The present review focuses on the neuronal composition and the internal signaling in the LHb. Morphologically six distinct types of neurons (spherical, fusiform-1, fusiform-2, polymorphic, vertical, neurogliaform) can be identified...
July 23, 2017: Pharmacology, Biochemistry, and Behavior
https://www.readbyqxmd.com/read/28702127/coordinating-heart-morphogenesis-a-novel-role-for-hyperpolarization-activated-cyclic-nucleotide-gated-hcn-channels-during-cardiogenesis-in-xenopus-laevis
#17
Emily Pitcairn, Hannah Harris, Justine Epiney, Vaibhav P Pai, Joan M Lemire, Bin Ye, Nian-Qing Shi, Michael Levin, Kelly A McLaughlin
Hyperpolarization-activated cyclic-nucleotide gated channel (HCN) proteins are important regulators of both neuronal and cardiac excitability. Among the 4 HCN isoforms, HCN4 is known as a pacemaker channel, because it helps control the periodicity of contractions in vertebrate hearts. Although the physiological role of HCN4 channel has been studied in adult mammalian hearts, an earlier role during embryogenesis has not been clearly established. Here, we probe the embryonic roles of HCN4 channels, providing the first characterization of the expression profile of any of the HCN isoforms during Xenopus laevis development and investigate the consequences of altering HCN4 function on embryonic pattern formation...
2017: Communicative & Integrative Biology
https://www.readbyqxmd.com/read/28690143/the-brain-penetrant-5-ht7-receptor-agonist-lp-211-reduces-the-sensory-and-affective-components-of-neuropathic-pain
#18
Mirko Santello, Alberto Bisco, Natalie Elisabeth Nevian, Enza Lacivita, Marcello Leopoldo, Thomas Nevian
Neuropathic pain is a debilitating pathological condition of high clinical relevance. Changes in neuronal excitability in the anterior cingulate cortex (ACC) play a central role in the negative emotional and affective aspects of chronic pain. We evaluated the effects of LP-211, a new serotonin-receptor-type-7 (5-HT7R) agonist that crosses the blood-brain barrier, on ACC neurons in a mouse model of neuropathic pain. LP-211 reduced synaptic integration in layer 5 pyramidal neurons, which was enhanced in neuropathic pain due to a dysfunction of dendritic hyperpolarization-activated-and-cyclic-nucleotide-regulated (HCN) channels...
October 2017: Neurobiology of Disease
https://www.readbyqxmd.com/read/28685234/prostanoid-ep3-receptor-agonist-sulprostone-enhances-pacemaker-activity-of-colonic-interstitial-cells-of-cajal
#19
Man Woo Kim, Han Yi Jiao, Seok Won Kim, Chan Guk Park, Mei Jin Wu, Chansik Hong, Seok Choi, Jae Yeoul Jun
EP receptor activation by PGE2 regulates gastrointestinal motility by modulating smooth muscle contractility. Interstitial cells of Cajal (ICCs) are pacemaker cells that regulate smooth muscle activity. We aimed to determine effects of the EP3 receptor agonist sulprostone on pacemaker potentials in colonic ICCs. We performed a whole cell patch clamp, RT-PCR, and Ca(2+) imaging in cultured ICCs from mouse colon. Sulprostone depolarized the membrane and increased pacemaker frequency. EP3 receptor antagonist blocked these sulprostone-induced effects...
July 6, 2017: Naunyn-Schmiedeberg's Archives of Pharmacology
https://www.readbyqxmd.com/read/28673721/contribution-of-presynaptic-hcn-channels-to-excitatory-inputs-of-spinal-substantia-gelatinosa-neurons
#20
S-C Peng, J Wu, D-Y Zhang, C-Y Jiang, C-N Xie, T Liu
Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are pathological pain-associated voltage-gated ion channels. They are widely expressed in central nervous system including spinal lamina II (also named the substantia gelatinosa, SG). Here, we examined the distribution of HCN channels in glutamatergic synaptic terminals as well as their role in the modulation of synaptic transmission in SG neurons from SD rats and glutamic acid decarboxylase-67 (GAD67)-GFP mice. We found that the expression of the HCN channel isoforms was varied in SG...
July 1, 2017: Neuroscience
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