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https://www.readbyqxmd.com/read/29047147/case-control-pharmacogenetic-study-of-hcn1-hcn2-variants-and-genetic-generalized-epilepsies
#1
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)...
October 19, 2017: Clinical and Experimental Pharmacology & Physiology
https://www.readbyqxmd.com/read/29046615/integrated-genomic-characterization-of-cancer-genes-in-glioma
#2
Aijun Liang, Bin Zhou, Wei Sun
BACKGROUND: Cancers are caused by the acquisition of somatic mutations. Numerous efforts have been made to characterize the key driver genes and pathways in glioma, however, the etiology of glioma is still not completely known. This study was implemented to characterize driver genes in glioma independently of somatic mutation frequencies. METHODS: Driver genes and pathways were predicted by OncodriveCLUST, OncodriveFM, Icages, Drgap and Dendrix in glioma using 31,958 somatic mutations from TCGA, followed by an integrative characterization of driver genes...
2017: Cancer Cell International
https://www.readbyqxmd.com/read/28989025/aav-mediated-conversion-of-human-pluripotent-stem-cell-derived-pacemaker
#3
Patrick K W Chan, Lin Geng, Yi Gao, Wendy Keung, Ronald A Li
Malfunction of nodal pacemaker (Pm) cardiomyocytes (CMs) due to diseases or aging leads to rhythm generation disorders, necessitating electronic Pm implantation. We functionally reprogrammed human pluripotent stem cell (hPSC) derived-ventricular (V) CMs into -PmCMs via recombinant adeno-associated virus serotype 9 (rAAV9)-mediated overexpression of engineered HCN1 channel (HCN1ΔΔΔ) whose S3-S4 linker has been strategically deleted by design to promote cardiac pacemaking. rAAV9-HCN1ΔΔΔ-reprogrammed hPSC-PmCMs converted from -VCMs showed automaticity and action potential parameters typical of native nodal PmCMs...
December 9, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28880996/dravet-syndrome-and-its-mimics-beyond-scn1a
#4
REVIEW
Dora Steel, Joseph D Symonds, Sameer M Zuberi, Andreas Brunklaus
OBJECTIVE: Dravet syndrome (DS) is a severe developmental and epileptic encephalopathy characterized by the onset of prolonged febrile and afebrile seizures in infancy, and evolving to drug-resistant epilepsy with accompanying cognitive, behavioral, and motor impairment. Most cases are now known to be caused by pathogenic variants in the sodium channel gene SCN1A, but several other genes have also been implicated. This review examines current understanding of the role of non-SCN1A genes in DS, and what is known about phenotypic similarities and differences...
November 2017: Epilepsia
https://www.readbyqxmd.com/read/28878030/the-hyperpolarization-activated-cyclic-nucleotide-gated-channels-from-biophysics-to-pharmacology-of-a-unique-family-of-ion-channels
#5
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/28871229/gabapentin-modulates-hcn4-channel-voltage-dependence
#6
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/28855177/small-functional-if-current-in-sinoatrial-pacemaker-cells-of-the-brown-trout-salmo-trutta-fario-heart-despite-strong-expression-of-hcn-channel-transcripts
#7
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/28467171/down-regulation-of-t-type-cav3-2-channels-by-hyperpolarization-activated-cyclic-nucleotide-gated-channel-1-hcn1-evidence-of-a-signaling-complex
#8
Jing Fan, Maria A Gandini, Fang-Xiong Zhang, Lina Chen, Ivana A Souza, Gerald W Zamponi
Formation of complexes between ion channels is important for signal processing in the brain. Here we investigate the biochemical and biophysical interactions between HCN1 channels and Cav3.2 T-type channels. We found that HCN1 co-immunoprecipitated with Cav3.2 from lysates of either mouse brain or tsA-201 cells, with the HCN1 N-terminus associating with the Cav3.2 N-terminus. Cav3.2 channel activity appeared to be functionally regulated by HCN1. The expression of HCN1 induced a decrease in Cav3.2 Ba(2+) influx (IBa(2+)) along with altered channel kinetics and a depolarizing shift in activation gating...
September 3, 2017: Channels
https://www.readbyqxmd.com/read/28455536/cation-and-voltage-dependence-of-lidocaine-inhibition-of-the-hyperpolarization-activated-cyclic-nucleotide-gated-hcn1-channel
#9
Igor Putrenko, Raymond Yip, Stephan K W Schwarz, Eric A Accili
Lidocaine is known to inhibit the hyperpolarization-activated mixed cation current (Ih) in cardiac myocytes and neurons, as well in cells transfected with cloned Hyperpolarization-activated Cyclic Nucleotide-gated (HCN) channels. However, the molecular mechanism of Ih inhibition by this drug has been limitedly explored. Here, we show that inhibition of Ih by lidocaine, recorded from Chinese hamster ovary (CHO) cells expressing the HCN1 channel, reached a steady state within one minute and was reversible. Lidocaine inhibition of Ih was greater at less negative voltages and smaller current amplitudes whereas the voltage-dependence of Ih activation was unchanged...
April 28, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28428632/cyclophosphamide-induced-hcn1-channel-upregulation-in-interstitial-cajal-like-cells-leads-to-bladder-hyperactivity-in-mice
#10
Qian Liu, Zhou Long, Xingyou Dong, Teng Zhang, Jiang Zhao, Bishao Sun, Jingzhen Zhu, Jia Li, Qingqing Wang, Zhenxing Yang, Xiaoyan Hu, Longkun Li
Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are confirmed to be expressed in bladder interstitial Cajal-like cells (ICC-LCs), but little is known about their possible role in cystitis-associated bladder dysfunction. The present study aimed to determine the functional role of HCN channels in regulating bladder function under inflammatory conditions. Sixty female wild-type C57BL/6J mice and sixty female HCN1-knockout mice were randomly assigned to experimental and control groups, respectively...
April 21, 2017: Experimental & Molecular Medicine
https://www.readbyqxmd.com/read/28416809/perisomatic-changes-in-h-channels-regulate-depressive-behaviors-following-chronic-unpredictable-stress
#11
C S Kim, D H Brager, D Johnston
Chronic stress can be a precipitating factor in the onset of depression. Lentiviral-mediated knockdown of HCN1 protein expression and reduction of functional Ih produce antidepressant behavior. However, whether h-channels are altered in an animal model of depression is not known. We found that perisomatic HCN1 protein expression and Ih-sensitive physiological measurements were significantly increased in dorsal but not in ventral CA1 region/neurons following chronic unpredictable stress (CUS), a widely accepted model for major depressive disorder...
April 18, 2017: Molecular Psychiatry
https://www.readbyqxmd.com/read/28363781/hyperpolarization-activated-current-ih-in-mouse-trigeminal-sensory-neurons-in-a-transgenic-mouse-model-of-familial-hemiplegic-migraine-type-1
#12
Francesca Eroli, Sandra Vilotti, Arn M J M van den Maagdenberg, Andrea Nistri
Transgenic knock-in (KI) mice that express CaV2.1 channels containing an R192Q gain-of-function mutation in the α1A subunit known to cause familial hemiplegic migraine type-1 in patients, exhibit key disease characteristics and provide a useful tool to investigate pathophysiological mechanisms of pain transduction. Previously, KI trigeminal sensory neurons were shown to exhibit constitutive hyperexcitability due to up-regulation of ATP-gated P2X3 receptors that trigger spike activity at a more negative threshold...
March 29, 2017: Neuroscience
https://www.readbyqxmd.com/read/28205043/a-polygenic-risk-score-for-breast-cancer-risk-in-a-taiwanese-population
#13
Yi-Chen Hsieh, Shih-Hsin Tu, Chien-Tien Su, Er-Chieh Cho, Chih-Hsiung Wu, Mao-Chih Hsieh, Shiyng-Yu Lin, Yun-Ru Liu, Chin-Sheng Hung, Hung-Yi Chiou
BACKGROUND: Multiple common variants identified by genome-wide association studies showed limited evidence of the risk of breast cancer in Taiwan. In this study, we analyzed the breast cancer risk in relation to 13 individual single-nucleotide polymorphisms (SNPs) identified by a GWAS in an Asian population. METHODS: In total, 446 breast cancer patients and 514 healthy controls were recruited for this case-control study. In addition, we developed a polygenic risk score (PRS) including those variants significantly associated with breast cancer risk, and also evaluated the contribution of PRS and clinical risk factors to breast cancer using receiver operating characteristic curve (AUC)...
February 15, 2017: Breast Cancer Research and Treatment
https://www.readbyqxmd.com/read/28178648/polymorphisms-of-esr1-ugt1a1-hcn1-map3k1-and-cyp2b6-are-associated-with-the-prognosis-of-hormone-receptor-positive-early-breast-cancer
#14
Sung-Hsin Kuo, Shi-Yi Yang, San-Lin You, Huang-Chun Lien, Ching-Hung Lin, Po-Han Lin, Chiun-Sheng Huang
In this study, we investigated whether single nucleotide polymorphisms (SNPs) identified by genome-wide association study (GWAS) (MAP3K1, FGFR2, TNRC9, HCN1, and 5p12), and SNPs involved in the metabolism of estrogen (CYP19, COMT, ESR1, and UGT1A1), tamoxifen (CYP2C9, CYP2C19, CYP3A5, and CYP2D6), and chemotherapeutic agents (ABCB1, ALDH3A1, and CYP2B6) are associated with the prognoses of 414 hormone receptor (HR)-positive early breast cancers with negative or 1 to 3 nodal metastases. At a median follow-up period of 10...
March 28, 2017: Oncotarget
https://www.readbyqxmd.com/read/28177679/reduced-expression-of-hcn-channels-in-the-sinoatrial-node-of-streptozotocin-induced-diabetic-rats
#15
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 the risk of arrhythmias. However, knowledge of electrical remodeling in the 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...
May 2017: Canadian Journal of Physiology and Pharmacology
https://www.readbyqxmd.com/read/28131828/ep3-activation-facilitates-bladder-excitability-via-hcn-channels-on-iccs
#16
Chao Wu, Xingyou Dong, Qian Liu, Jingzhen Zhu, Teng Zhang, Qingqing Wang, Xiaoyang Hu, Zhenxing Yang, Longkun Li
EP3 is a receptor for prostaglandin E2 (PGE2), and although its effect on bladder excitability has attracted considerable attention, the underlying mechanism remains unclear. To investigate whether the hyperpolarization-activated cyclic nucleotide-gated (HCN) channels in the interstitial cells of Cajal (ICCs) of the bladder are involved in the effect of EP3 activation on bladder excitability, wild-type mice, HCN1 knockout (HCN1(-/-)) mice and rats were used in our study. Double immunofluorescence staining and immunoprecipitation assays demonstrated the interaction between EP3 and the HCN channels...
April 1, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28088409/genome-wide-association-analysis-and-pathways-enrichment-for-lactation-persistency-in-canadian-holstein-cattle
#17
D N Do, N Bissonnette, P Lacasse, F Miglior, M Sargolzaei, X Zhao, E M Ibeagha-Awemu
Lactation persistency (LP), defined as the rate of declining milk yield after milk peak, is an economically important trait for dairy cattle. Improving LP is considered a good alternative method for increasing overall milk production because it does not cause the negative energy balance and other health issues that cows experience during peak milk production. However, little is known about the biology of LP. A genome-wide association study (GWAS) and pathway enrichment were used to explore the genetic mechanisms underlying LP...
March 2017: Journal of Dairy Science
https://www.readbyqxmd.com/read/28071723/hcn1-channels-reduce-the-rate-of-exocytosis-from-a-subset-of-cortical-synaptic-terminals
#18
Zhuo Huang, Gengyu Li, Carolina Aguado, Rafael Lujan, Mala M Shah
The hyperpolarization-activated cyclic nucleotide-gated (HCN1) channels are predominantly located in pyramidal cell dendrites within the cortex. Recent evidence suggests these channels also exist pre-synaptically in a subset of synaptic terminals within the mature entorhinal cortex (EC). Inhibition of pre-synaptic HCN channels enhances miniature excitatory post-synaptic currents (mEPSCs) onto EC layer III pyramidal neurons, suggesting that these channels decrease the release of the neurotransmitter, glutamate...
January 10, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28050647/deleting-the-hcn1-subunit-of-hyperpolarization-activated-ion-channels-in-mice-impairs-acoustic-startle-reflexes-gap-detection-and-spatial-localization
#19
James R Ison, Paul D Allen, Donata Oertel
It has been proposed that the high temporal and spatial acuities of human listeners and animals tested in the hearing laboratory depend in part on the short time constants of auditory neurons that are able to preserve or sharpen the information conveyed in the timing of firing of auditory nerve fibers. We tested this hypothesis in a series of in vivo experiments, based on previous in vitro experiments showing that neuronal time constants are raised in brainstem slices when HCN1 channels are blocked or in slices obtained from Hcn1 (-/-) null mutant mice...
June 2017: Journal of the Association for Research in Otolaryngology: JARO
https://www.readbyqxmd.com/read/27979911/atrioventricular-node-dysfunction-and-ion-channel-transcriptome-in-pulmonary-hypertension
#20
Ian P Temple, Sunil Jit R J Logantha, Mais Absi, Yu Zhang, Eleftheria Pervolaraki, Joseph Yanni, Andrew Atkinson, Maria Petkova, Gillian M Quigley, Simon Castro, Mark Drinkhill, Heiko Schneider, Oliver Monfredi, Elizabeth Cartwright, Min Zi, Tomoko T Yamanushi, Vaikom S Mahadevan, Alison M Gurney, Ed White, Henggui Zhang, George Hart, Mark R Boyett, Halina Dobrzynski
BACKGROUND: Heart block is associated with pulmonary hypertension, and the aim of the study was to test the hypothesis that the heart block is the result of a change in the ion channel transcriptome of the atrioventricular (AV) node. METHODS AND RESULTS: The most commonly used animal model of pulmonary hypertension, the monocrotaline-injected rat, was used. The functional consequences of monocrotaline injection were determined by echocardiography, ECG recording, and electrophysiological experiments on the Langendorff-perfused heart and isolated AV node...
December 2016: Circulation. Arrhythmia and Electrophysiology
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