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K Sugahara, Y Maeda, K Shimano, A Mogami, H Kataoka, K Ogawa, K Hikida, H Kumagai, M Asayama, T Yamamoto, T Harada, P Ni, S Inoue, A Kawaguchi
BACKGROUND AND PURPOSE: We conducted preclinical and clinical studies to examine the pharmacological, particularly cardiac, effects of amiselimod (MT-1303), a second-generation sphingosine 1-phosphate (S1P) receptor modulator, designed to reduce the bradycardia effects associated with fingolimod and other S1P receptor modulators. EXPERIMENTAL APPROACH: The selectivity of the active metabolite amiselimod phosphate (amiselimod-P) for human S1P receptors and activation of the G-protein-coupled inwardly rectifying potassium (GIRK) channel in human atrial myocytes were assessed...
October 7, 2016: British Journal of Pharmacology
Sudarat Nimitvilai, Chang You, Devinder S Arora, Maureen A McElvain, Bertha J Vandegrift, Mark S Brodie, John J Woodward
Drugs of abuse increase the activity of dopaminergic neurons of the ventral tegmental area (VTA), and output from the VTA is critical for both natural and drug-induced reward and reinforcement. Ethanol and the abused inhalant toluene both enhance VTA neuronal firing, but the mechanisms of this effect is not fully known. In this study, we used extracellular recordings to compare the actions of toluene and ethanol on DA VTA neurons. Both ethanol and toluene increased the firing rate of DA neurons, although toluene was ~100 times more potent than ethanol...
2016: Frontiers in Neuroscience
Nicole Arnold, Thomas Girke, Suhas Sureshchandra, Ilhem Messaoudi
: Primary infection with varicella zoster virus (VZV), a neurotropic alpha herpesvirus, results in varicella. VZV establishes latency in the sensory ganglia and can reactivate later in life to cause herpes zoster. The relationship between VZV and its host during acute infection in the sensory ganglia is not well understood due to limited access to clinical specimens. Intrabronchial inoculation of rhesus macaques with simian varicella virus (SVV), recapitulates the hallmarks of VZV infection in humans...
September 28, 2016: Journal of Virology
Nicole Arnold, Thomas Girke, Suhas Sureshchandra, Christina Nguyen, Maham Rais, Ilhem Messaoudi
Varicella Zoster Virus (VZV) is the causative agent of varicella and herpes zoster. Although it is well established that VZV is transmitted via the respiratory route, the host-pathogen interactions during acute VZV infection in the lungs remain poorly understood due to limited access to clinical samples. To address these gaps in our knowledge, we leveraged a nonhuman primate model of VZV infection where rhesus macaques are intrabronchially challenged with the closely related Simian Varicella Virus (SVV). Acute infection is characterized by immune infiltration of the lung airways, a significant up-regulation of genes involved in antiviral-immunity, and a down-regulation of genes involved in lung development...
September 28, 2016: Scientific Reports
Tyler W H Backman, Thomas Girke
BACKGROUND: Next-generation sequencing (NGS) has revolutionized how research is carried out in many areas of biology and medicine. However, the analysis of NGS data remains a major obstacle to the efficient utilization of the technology, as it requires complex multi-step processing of big data demanding considerable computational expertise from users. While substantial effort has been invested on the development of software dedicated to the individual analysis steps of NGS experiments, insufficient resources are currently available for integrating the individual software components within the widely used R/Bioconductor environment into automated workflows capable of running the analysis of most types of NGS applications from start-to-finish in a time-efficient and reproducible manner...
2016: BMC Bioinformatics
Matthias Kröz, Marcus Reif, Danilo Pranga, Roland Zerm, Friedemann Schad, Erik Wim Baars, Matthias Girke
The concept of autonomic regulation (aR) reflects the relevance of the function of different autonomic systems for health. aR can be captured by questionnaires. We differentiate between a trait or constitutional aR questionnaire version including 12 (short-version) or 18 items, respectively, with three subscales (orthostatic-circulatory, rest/activity and digestive regulation), and an 18-item state aR questionnaire on the preceding week with four subscales (rest/activity, orthostatic-circulatory, thermo- and digestive regulation)...
September 2016: Journal of Integrative Medicine
Gaspard Montandon, Hattie Liu, Richard L Horner
Breathing is generated by a respiratory network in the brainstem. At its core, a population of neurons expressing neurokinin-1 receptors (NK1R) and the peptide somatostatin (SST) form the preBötzinger Complex (preBötC), a site essential for the generation of breathing. PreBötC interneurons generate rhythm and follower neurons shape motor outputs by activating upper airway respiratory muscles. Since NK1R-expressing preBötC neurons are preferentially inhibited by μ-opioid receptors via activation of GIRK channels, NK1R stimulation may also involve GIRK channels...
2016: Scientific Reports
S Rezania, S Kammerer, C Li, B Steinecker-Frohnwieser, A Gorischek, T T J DeVaney, S Verheyen, C A Passegger, N Ghaffari Tabrizi-Wizsy, H Hackl, D Platzer, A H Zarnani, E Malle, S W Jahn, T Bauernhofer, W Schreibmayer
BACKGROUND: Overexpression the KCNJ3, a gene that encodes subunit 1 of G-protein activated inwardly rectifying K(+) channel (GIRK1) in the primary tumor has been found to be associated with reduced survival times and increased lymph node metastasis in breast cancer patients. METHODS: In order to survey possible tumorigenic properties of GIRK1 overexpression, a range of malignant mammary epithelial cells, based on the MCF-7 cell line that permanently overexpress different splice variants of the KCNJ3 gene (GIRK1a, GIRK1c, GIRK1d and as a control, eYFP) were produced...
2016: BMC Cancer
Yun Lu, Chang-Jun Li, Cheng Chen, Pan Luo, Mei Zhou, Cai Li, Xu-Lin Xu, Qing Lu, Zhi He, Lian-Jun Guo
Anxiety is an affective disorder that is commonly observed after irreversible brain damage induced by cerebral ischemia and can delay the physical and cognitive recovery, which affects the quality of life of both the patient and family members. However, anxiety after ischemia has received less attention, and mechanisms underlying anxiety-like behaviours induced by chronic cerebral ischemia are under-investigated. In the present study, the chronic cerebral hypoperfusion model was established by the permanent occlusion of the bilateral common carotid arteries (two-vessel occlusion, 2VO) in rats, and anxiety-related behaviours were evaluated...
November 2016: Neuropharmacology
Nora M McCall, Lydia Kotecki, Sergio Dominguez-Lopez, Ezequiel Marron Fernandez de Velasco, Nicholas Carlblom, Amanda L Sharpe, Michael J Beckstead, Kevin Wickman
The increase in dopamine (DA) neurotransmission stimulated by in vivo cocaine exposure is tempered by G protein-dependent inhibitory feedback mechanisms in DA neurons of the ventral tegmental area (VTA). G protein-gated inwardly rectifying K(+) (GIRK/Kir3) channels mediate the direct inhibitory effect of GABAB receptor (GABABR) and D2 DA receptor (D2R) activation in VTA DA neurons. Here, we examined the effect of the DA neuron-specific loss of GIRK channels on D2R-dependent regulation of VTA DA neuron excitability and on cocaine-induced, reward-related behaviors...
July 29, 2016: Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology
Krutika Joshi, Lily Shen, Avner Michaeli, Michael Salter, Gabrielle Thibault-Messier, Sumaiya Hashmi, James H Eubanks, Miguel A Cortez, O Carter Snead
OBJECTIVE: The Ts65Dn (Ts) mouse model of Down syndrome (DS) is exquisitely sensitive to an infantile spasms phenotype induced by γ-aminobutyric acidB receptor (GABAB R) agonists. The Ts mouse contains the core genomic triplication of the DS critical region, which includes 3 copies of the Kcnj6 gene that encodes the GABAB R-coupled G protein-coupled inward rectifying potassium channel subunit 2 (GIRK2) channel. We test the hypothesis that GIRK2 is necessary for the GABAB R agonist-induced infantile spasms phenotype in Ts...
October 2016: Annals of Neurology
Ning Li, Thomas A Csepe, Brian J Hansen, Lidiya V Sul, Anuradha Kalyanasundaram, Stanislav O Zakharkin, Jichao Zhao, Avirup Guha, David R Van Wagoner, Ahmet Kilic, Peter J Mohler, Paul M L Janssen, Brandon J Biesiadecki, John D Hummel, Raul Weiss, Vadim V Fedorov
BACKGROUND: Adenosine provokes atrial fibrillation (AF) with a higher activation frequency in right atria (RA) versus left atria (LA) in patients, but the underlying molecular and functional substrates are unclear. We tested the hypothesis that adenosine-induced AF is driven by localized reentry in RA areas with highest expression of adenosine A1 receptor and its downstream GIRK (G protein-coupled inwardly rectifying potassium channels) channels (IK,Ado). METHODS: We applied biatrial optical mapping and immunoblot mapping of various atrial regions to reveal the mechanism of adenosine-induced AF in explanted failing and nonfailing human hearts (n=37)...
August 9, 2016: Circulation
Andrea Vasas, Peter Forgo, Péter Orvos, László Tálosi, Attila Csorba, Gyula Pinke, Judit Hohmann
GIRK channels are activated by a large number of G protein-coupled receptors and regulate the electrical activity of neurons, cardiac atrial myocytes, and β-pancreatic cells. Abnormalities in GIRK channel function have been implicated in the pathophysiology of neuropathic pain, drug addiction, and cardiac arrhythmias. In the heart, GIRK channels are selectively expressed in the atrium, and their activation inhibits pacemaker activity, thereby slowing the heart rate. In the present study, 19 new diterpenes, falcatins A-S (1-19), and the known euphorprolitherin D (20) were isolated from Euphorbia falcata...
August 26, 2016: Journal of Natural Products
Aphroditi A Mamaligas, Christopher P Ford
Cholinergic interneurons (CHIs) play a major role in motor and learning functions of the striatum. As acetylcholine does not directly evoke postsynaptic events at most striatal synapses, it remains unclear how postsynaptic cholinergic receptors encode the firing patterns of CHIs in the striatum. To examine the dynamics of acetylcholine release, we used optogenetics and paired recordings from CHIs and medium spiny neurons (MSNs) virally overexpressing G-protein-activated inwardly rectifying potassium (GIRK) channels...
August 3, 2016: Neuron
Tyler William H Backman, Thomas Girke
Despite a large and rapidly growing body of small molecule bioactivity screens available in the public domain, systematic leverage of the data to assess target druggability and compound selectivity has been confounded by a lack of suitable cross-target analysis software. We have developed bioassayR, a computational tool that enables simultaneous analysis of thousands of bioassay experiments performed over a diverse set of compounds and biological targets. Unique features include support for large-scale cross-target analyses of both public and custom bioassays, generation of high throughput screening fingerprints (HTSFPs), and an optional preloaded database that provides access to a substantial portion of publicly available bioactivity data...
July 25, 2016: Journal of Chemical Information and Modeling
Stephanie Constantin, Susan Wray
GnRH neurons are regulated by hypothalamic kisspeptin neurons. Recently, galanin was identified in a subpopulation of kisspeptin neurons. Although the literature thoroughly describes kisspeptin activation of GnRH neurons, little is known about the effects of galanin on GnRH neurons. This study investigated whether galanin could alter kisspeptin signaling to GnRH neurons. GnRH cells maintained in explants, known to display spontaneous calcium oscillations, and a long-lasting calcium response to kisspeptin-10 (kp-10), were used...
August 2016: Endocrinology
Yea Lu Tay, Yi Fan Teah, Yoong Min Chong, Mohd Fadzly Amar Jamil, Sina Kollert, Mohd Ilham Adenan, Habibah Abdul Wahab, Frank Döring, Erhard Wischmeyer, Mei Lan Tan
Mitragyna speciosa Korth is known for its euphoric properties and is frequently used for recreational purposes. Several poisoning and fatal cases involving mitragynine have been reported but the underlying causes remain unclear. Human ether-a-go-go-related gene (hERG) encodes the cardiac IKr current which is a determinant of the duration of ventricular action potentials and QT interval. On the other hand, IK1, a Kir current mediated by Kir2.1 channel and IKACh, a receptor-activated Kir current mediated by GIRK channel are also known to be important in maintaining the cardiac function...
August 15, 2016: Toxicology and Applied Pharmacology
Hans Van Veen, Divya Vashisht, Melis Akman, Thomas Girke, Angelika Mustroph, Emilie Reinen, Sjon Hartman, Maarten Kooiker, Peter van Tienderen, M Eric Schranz, Julia Bailey-Serres, Laurentius A C J Voesenek, Rashmi Sasidharan
Climate change has increased the frequency and severity of flooding events with significant negative impact on agricultural productivity. These events often submerge plant aerial organs and roots, limiting growth and survival due to a severe reduction in light reactions and gas exchange necessary for photosynthesis and respiration, respectively. To distinguish molecular responses to the compound stress imposed by submergence, we investigated transcriptomic adjustments to darkness in air and under submerged conditions using eight Arabidopsis thaliana accessions differing significantly in sensitivity to submergence...
May 15, 2016: Plant Physiology
Christopher Miller
Experiments on artificial membranes are revealing many details about the workings of a family of potassium ion channels called GIRK channels.
2016: ELife
Jutta Girke, Claudia Seipt, Andrea Markowski, Birgit Luettig, Anika Schettler, Michael Momma, Andrea S Schneider
BACKGROUND: Patients with end-stage cancer and advanced chronic bowel disease are often malnourished, which has a negative effect on patients' outcome, well-being, and activity. It is inconclusive whether these patients benefit from home parenteral nutrition. This prospective exploratory study investigates its influence on nutrition state, muscle strength, mobility, and quality of life. MATERIALS AND METHODS: Patients ≥18 years old with an indication for home parenteral nutrition were included and followed for 2-24 months...
October 2016: Nutrition in Clinical Practice
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