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https://www.readbyqxmd.com/read/27911380/method-for-identifying-small-molecule-inhibitors-of-the-protein-protein-interaction-between-hcn1-and-trip8b
#1
Ye Han, Kyle A Lyman, Matt Clutter, Gary E Schiltz, Quratul-Ain Ismail, Xiangying Cheng, Chi-Hao Luan, Dane M Chetkovich
Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are expressed ubiquitously throughout the brain, where they function to regulate the excitability of neurons. The subcellular distribution of these channels in pyramidal neurons of hippocampal area CA1 is regulated by tetratricopeptide repeat-containing Rab8b interacting protein (TRIP8b), an auxiliary subunit. Genetic knockout of HCN pore forming subunits or TRIP8b, both lead to an increase in antidepressant-like behavior, suggesting that limiting the function of HCN channels may be useful as a treatment for Major Depressive Disorder (MDD)...
November 11, 2016: Journal of Visualized Experiments: JoVE
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
#2
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...
November 25, 2016: Oncotarget
https://www.readbyqxmd.com/read/27813693/loss-of-hcn-channel-mediated-ih-current-following-seizures-accounts-for-movement-dysfunction
#3
Jeffery A Boychuk, G Campbell Teskey
No abstract text is available yet for this article.
November 4, 2016: Channels
https://www.readbyqxmd.com/read/27807172/nitric-oxide-modulates-hcn-channels-in-magnocellular-neurons-of-the-supraoptic-nucleus-of-rats-by-an-s-nitrosylation-dependent-mechanism
#4
Melina Pires da Silva, Davi José de Almeida Moraes, André de Souza Mecawi, José Antunes Rodrigues, Wamberto Antonio Varanda
: The control of the excitability in magnocellular neurosecretory cells (MNCs) of the supraoptic nucleus has been attributed mainly to synaptic inputs from circunventricular organs. However, nitric oxide (NO), a gaseous messenger produced in this nucleus during isotonic and short-term hypertonic conditions, is an example of a modulator that can act directly on MNCs to modulate their firing rate. NO inhibits the electrical excitability of MNCs, leading to a decrease in the release of vasopressin and oxytocin...
November 2, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/27743933/contribution-of-large-sized-primary-sensory-neuronal-sensitization-to-mechanical-allodynia-by-upregulation-of-hyperpolarization-activated-cyclic-nucleotide-gated-channels-via-cyclooxygenase-1-cascade
#5
Wei Sun, Fei Yang, Yan Wang, Han Fu, Yan Yang, Chun-Li Li, Xiao-Liang Wang, Qing Lin, Jun Chen
Under physiological state, small- and medium-sized dorsal root ganglia (DRG) neurons are believed to mediate nociceptive behavioral responses to painful stimuli. However, recently it has been found that a number of large-sized neurons are also involved in nociceptive transmission under neuropathic conditions. Nonetheless, the underlying mechanisms that large-sized DRG neurons mediate nociception are poorly understood. In the present study, the role of large-sized neurons in bee venom (BV)-induced mechanical allodynia and the underlying mechanisms were investigated...
October 12, 2016: Neuropharmacology
https://www.readbyqxmd.com/read/27690448/structural-basis-of-tonic-inhibition-by-dimers-of-dimers-in-hyperpolarization-activated-cyclic-nucleotide-modulated-hcn-ion-channels
#6
Bryan VanSchouwen, Giuseppe Melacini
The hyperpolarization-activated cyclic-nucleotide-modulated (HCN) ion channels control rhythmicity in neurons and cardiomyocytes. Cyclic AMP (cAMP) modulates HCN activity through cAMP-dependent formation of a tetrameric gating ring spanning the intracellular region (IR) of HCN. In the absence of cAMP, the IR cAMP-binding domain (CBD) mainly samples its inactive conformation, resulting in steric clashes that destabilize the IR tetramer. Although these clashes with the inactive CBD are released through tetramer dissociation into monomers, functional mutagenesis suggests that the apo IR is not fully monomeric...
October 3, 2016: Journal of Physical Chemistry. B
https://www.readbyqxmd.com/read/27668045/corlanor-ivabradine-first-hcn-channel-blocker-fda-approved-for-the-treatment-of-patients-with-heart-failure
#7
Loretta Fala
No abstract text is available yet for this article.
March 2016: American Health & Drug Benefits
https://www.readbyqxmd.com/read/27650422/central-neural-alterations-predominate-in-an-insect-model-of-nociceptive-sensitization
#8
Dennis R Tabuena, Allan Solis, Ken Geraldi, Christopher A Moffatt, Megumi Fuse
Many organisms respond to noxious stimuli with defensive maneuvers. This is noted in the hornworm, Manduca sexta, as a defensive strike response. After tissue damage, organisms typically display sensitized responses to both noxious or normally innocuous stimuli. To further understand this phenomenon, we used novel in situ and in vitro preparations based on paired extracellular nerve recordings and videography to identify central and peripheral nerves responsible for nociception and sensitization of the defensive behavior in M...
September 21, 2016: Journal of Comparative Neurology
https://www.readbyqxmd.com/read/27633787/accumulation-of-k-in-the-synaptic-cleft-modulates-activity-by-influencing-both-vestibular-hair-cell-and-calyx-afferent-in-the-turtle
#9
Donatella Contini, Steven D Price, Jonathan J Art
KEY POINTS: In the synaptic cleft between type I hair cells and calyceal afferents, K(+) ions accumulate as a function of activity, dynamically altering the driving force and permeation through ion channels facing the synaptic cleft. High-fidelity synaptic transmission is possible due to large conductances that minimize hair cell and afferent time constants in the presence of significant membrane capacitance. Elevated potassium maintains hair cells near a potential where transduction currents are sufficient to depolarize them to voltages necessary for calcium influx and synaptic vesicle fusion...
September 16, 2016: Journal of Physiology
https://www.readbyqxmd.com/read/27621481/hcn2-ion-channels-basic-science-opens-up-possibilities-for-therapeutic-intervention-in-neuropathic-pain
#10
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/27585751/activation-of-5-ht2a-2c-receptors-reduces-the-excitability-of-cultured-cortical-neurons
#11
Lingli Hu, Chunhua Liu, Minyan Dang, Bin Luo, Yiping Guo, Haitao Wang
The abundant forebrain serotonergic projections are believed to modulate the activities of cortical neurons. 5-HT2 receptor among multiple subtypes of serotonin receptors contributes to the modulation of excitability, synaptic transmissions and plasticity. In the present study, whole-cell patch-clamp recording was adopted to examine whether activation of 5-HT2A/2C receptors would have any impact on the excitability of cultured cortical neurons. We found that 2,5-Dimethoxy-4-iodoamphetamine (DOI), a selective 5-HT2A/2C receptor agonist, rapidly and reversibly depressed spontaneous action potentials mimicking the effect of serotonin...
October 6, 2016: Neuroscience Letters
https://www.readbyqxmd.com/read/27583680/a-novel-intrinsic-analgesic-mechanism-the-enhancement-of-the-conduction-failure-along-polymodal-nociceptive-c-fibers
#12
Xiuchao Wang, Shan Wang, Wenting Wang, Jianhong Duan, Ming Zhang, Xiaohua Lv, Chunxiao Niu, Chao Tan, Yuanbin Wu, Jing Yang, Sanjue Hu, Junling Xing
Although conduction failure has been observed in nociceptive C-fibers, little is known regarding its significance or therapeutic potential. In a previous study, we demonstrated that C-fiber conduction failure, which is regarded as an intrinsic self-inhibition mechanism, was reduced in circumstances of painful diabetic neuropathy. In this study, we extend this finding in the complete Freund's adjuvant model of inflammatory pain and validate that the degree of conduction failure decreased and led to a greater amount of pain signals conveyed to the central nervous system...
October 2016: Pain
https://www.readbyqxmd.com/read/27569278/expression-and-cellular-localization-of-hcn-channels-in-rat-cerebellar-granule-neurons
#13
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/27568501/hcn-channels-segregate-stimulation-evoked-movement-responses-in-neocortex-and-allow-for-coordinated-forelimb-movements-in-rodents
#14
Jeffery A Boychuk, Jordan S Farrell, Laura A Palmer, Anna C Singleton, Quentin J Pittman, G Campbell Teskey
The mechanisms by which distinct movements of a forelimb are generated from the same area of motor cortex have remained elusive. Here we examined a role for HCN channels, given their ability to alter synaptic integration, in the expression of forelimb movement responses during intracortical microstimulation (ICMS) and movements of the forelimb on a skilled reaching task. We used short-duration high resolution ICMS to evoke forelimb movements following pharmacological (ZD7288), experimental (electrically induced cortical seizures) or genetic approaches that we confirmed with whole-cell patch clamp to substantially reduce Ih current...
August 29, 2016: Journal of Physiology
https://www.readbyqxmd.com/read/27556324/dysfunctional-hyperpolarization-activated-cyclic-nucleotide-gated-ion-channels-in-cardiac-diseases
#15
Xiaoqi Zhao, Tianxiang Gu
Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are reverse voltage-dependent, and their activation depends on the hyperpolarization of the membrane and may be directly or indirectly regulated by the cyclic adenosine monophosphate (cAMP) or other signal-transduction cascades. The distribution, quantity and activation states of HCN channels differ in tissues throughout the body. Evidence exhibits that HCN channels play critical roles in the generation and conduction of the electrical impulse and the physiopathological process of some cardiac diseases...
April 2016: Brazilian Journal of Cardiovascular Surgery
https://www.readbyqxmd.com/read/27553229/mutation-in-s6-domain-of-hcn4-channel-in-patient-with-suspected-brugada-syndrome-modifies-channel-function
#16
Stephanie Biel, Marco Aquila, Brigitte Hertel, Anne Berthold, Thomas Neumann, Dario DiFrancesco, Anna Moroni, Gerhard Thiel, Silke Kauferstein
Diseases such as the sick sinus and the Brugada syndrome are cardiac abnormalities, which can be caused by a number of genetic aberrances. Among them are mutations in HCN4, a gene, which encodes the hyperpolarization-activated, cyclic nucleotide-gated ion channel 4; this pacemaker channel is responsible for the spontaneous activity of the sinoatrial node. The present genetic screening of patients with suspected or diagnosed Brugada or sick sinus syndrome identified in 1 out of 62 samples the novel mutation V492F...
October 2016: Pflügers Archiv: European Journal of Physiology
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/27507948/chronic-treatment-with-ivabradine-does-not-affect-cardiovascular-autonomic-control-in-rats
#18
Fernanda C Silva, Franciny A Paiva, Flávia C Müller-Ribeiro, Henrique M A Caldeira, Marco A P Fontes, Rodrigo C A de Menezes, Karina R Casali, Gláucia H Fortes, Eleonora Tobaldini, Monica Solbiati, Nicola Montano, Valdo J Dias Da Silva, Deoclécio A Chianca
A low resting heart rate (HR) would be of great benefit in cardiovascular diseases. Ivabradine-a novel selective inhibitor of hyperpolarization-activated cyclic nucleotide gated (HCN) channels- has emerged as a promising HR lowering drug. Its effects on the autonomic HR control are little known. This study assessed the effects of chronic treatment with ivabradine on the modulatory, reflex and tonic cardiovascular autonomic control and on the renal sympathetic nerve activity (RSNA). Male Wistar rats were divided in 2 groups, receiving intraperitoneal injections of vehicle (VEH) or ivabradine (IVA) during 7 or 8 consecutive days...
2016: Frontiers in Physiology
https://www.readbyqxmd.com/read/27496876/hyperpolarization-activated-cyclic-nucleotide-gated-channels-in-peripheral-diaphragmatic-lymphatics
#19
Daniela Negrini, Cristiana Marcozzi, Eleonora Solari, Elena Bossi, Raffaella Cinquetti, Marcella Reguzzoni, Andrea Moriondo
Diaphragmatic lymphatic function is mainly sustained by pressure changes in the tissue and serosal cavities during cardiorespiratory cycles. The most peripheral diaphragmatic lymphatics are equipped with muscle cells (LMCs), which exhibit spontaneous contraction, whose molecular machinery is still undetermined. Hypothesizing that spontaneous contraction might involve hyperpolarization-activated cyclic nucleotide-gated (HCN) channels in lymphatic LMCs, diaphragmatic specimens, including spontaneously contracting lymphatics, were excised from 33 anesthetized rats, moved to a perfusion chamber containing HEPES-Tyrode's solution, and treated with HCN channels inhibitors cesium chloride (CsCl), ivabradine, and ZD-7288...
October 1, 2016: American Journal of Physiology. Heart and Circulatory Physiology
https://www.readbyqxmd.com/read/27464853/extracellular-potassium-and-seizures-excitation-inhibition-and-the-role-of-ih
#20
Lihua Wang, Suzie Dufour, Taufik A Valiante, Peter L Carlen
Seizure activity leads to increases in extracellular potassium concentration ([K[Formula: see text]]o), which can result in changes in neuronal passive and active membrane properties as well as in population activities. In this study, we examined how extracellular potassium modulates seizure activities using an acute 4-AP induced seizure model in the neocortex, both in vivo and in vitro. Moderately elevated [K[Formula: see text]]o up to 9[Formula: see text]mM prolonged seizure durations and shortened interictal intervals as well as depolarized the neuronal resting membrane potential (RMP)...
December 2016: International Journal of Neural Systems
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