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https://www.readbyqxmd.com/read/28528670/glycine-receptor-drug-discovery
#1
Joseph W Lynch, Yan Zhang, Sahil Talwar, Argel Estrada-Mondragon
Postsynaptic glycine receptor (GlyR) chloride channels mediate inhibitory neurotransmission in the spinal cord and brain stem, although presynaptic and extrasynaptic GlyRs are expressed more widely throughout the brain. In humans, GlyRs are assembled as homo- or heteromeric pentamers of α1-3 and β subunits. GlyR malfunctions have been linked to a range of neurological disorders including hyperekplexia, temporal lobe epilepsy, autism, breathing disorders, and chronic inflammatory pain. Although it is possible that GlyRs may eventually be clinically targeted for a variety of neurological disorders, most research to date has focused on developing GlyR-targeted treatments for chronic pain...
2017: Advances in Pharmacology
https://www.readbyqxmd.com/read/28514446/identification-of-preoptic-sleep-neurons-using-retrograde-labelling-and-gene-profiling
#2
Shinjae Chung, Franz Weber, Peng Zhong, Chan Lek Tan, Thuc Nghi Nguyen, Kevin T Beier, Nikolai Hörmann, Wei-Cheng Chang, Zhe Zhang, Johnny Phong Do, Shenqin Yao, Michael J Krashes, Bosiljka Tasic, Ali Cetin, Hongkui Zeng, Zachary A Knight, Liqun Luo, Yang Dan
In humans and other mammalian species, lesions in the preoptic area of the hypothalamus cause profound sleep impairment, indicating a crucial role of the preoptic area in sleep generation. However, the underlying circuit mechanism remains poorly understood. Electrophysiological recordings and c-Fos immunohistochemistry have shown the existence of sleep-active neurons in the preoptic area, especially in the ventrolateral preoptic area and median preoptic nucleus. Pharmacogenetic activation of c-Fos-labelled sleep-active neurons has been shown to induce sleep...
May 17, 2017: Nature
https://www.readbyqxmd.com/read/28496181/the-neuronal-k-cl-co-transporter-2-slc12a5-modulates-insulin-secretion
#3
Shams Kursan, Timothy S McMillen, Pavani Beesetty, Eduardo Dias-Junior, Mohammed M Almutairi, Abu A Sajib, J Ashot Kozak, Lydia Aguilar-Bryan, Mauricio Di Fulvio
Intracellular chloride concentration ([Cl(-)]i) in pancreatic β-cells is kept above electrochemical equilibrium due to the predominant functional presence of Cl(-) loaders such as the Na(+)K(+)2Cl(-) co-transporter 1 (Slc12a2) over Cl(-)extruders of unidentified nature. Using molecular cloning, RT-PCR, Western blotting, immunolocalization and in vitro functional assays, we establish that the "neuron-specific" K(+)Cl(-) co-transporter 2 (KCC2, Slc12a5) is expressed in several endocrine cells of the pancreatic islet, including glucagon secreting α-cells, but particularly in insulin-secreting β-cells, where we provide evidence for its role in the insulin secretory response...
May 11, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28479061/crystal-structures-of-human-glyr%C3%AE-3-bound-to-ivermectin
#4
Xin Huang, Hao Chen, Paul L Shaffer
Ivermectin acts as a positive allosteric modulator of several Cys-loop receptors including the glutamate-gated chloride channels (GluCls), γ-aminobutyric acid receptors (GABAARs), glycine receptors (GlyRs), and neuronal α7-nicotinic receptors (α7 nAChRs). The crystal structure of Caenorhabditis elegans GluCl complexed with ivermectin revealed the details of its ivermectin binding site. Although the electron microscopy structure of zebrafish GlyRα1 complexed with ivermectin demonstrated a similar binding orientation, detailed structural information on the ivermectin binding and pore opening for Cys-loop receptors in vertebrates has been elusive...
May 4, 2017: Structure
https://www.readbyqxmd.com/read/28470528/phenotyping-cellular-viability-by-functional-analysis-of-ion-channels-glyr-targeted-screening-in-nt2-n-cells
#5
Katharina Kuenzel, Sepideh Abolpour Mofrad, Daniel F Gilbert
Glycine receptor chloride channels (GlyRs) are attractive drug targets for therapeutic intervention and are also more and more recognized in the context of in vitro neurotoxicity and developmental neurotoxicity testing. Assaying the functional properties of GlyR can serve as an indicator of cellular viability and the integrity of the developing and mature central nervous system. Human pluripotent NTERA-2 (NT2) stem cells undergo neuronal differentiation upon stimulation with retinoic acid and express a large variety of neuronal proteins-including GlyR...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/28460564/effect-of-tpmpa-gabac-receptor-antagonist-on-neuronal-response-properties-in-rat-barrel-cortex
#6
Elham Mohammadi, Ali Shamsizadeh, Elham Salari, Iman Fatemi, Mohammad Allahtavakoli, Ali Roohbakhsh
GABAC receptors are ligand-gated chloride channels and have important roles in some neurological functions like vision. Recent investigations demonstrated that these receptors are also expressed in the somatosensory cortex. In this study, we investigated the effect of (1,2,5,6-tetrahydropyridin-4-yl)methylphosphinic acid (TPMPA) (GABAC receptor antagonist) on the properties of the neuronal response to natural stimuli (whisker deflection) in deep layers of rat barrel cortex. Twenty-eight male Wistar rats, weighing 230-260 g, were used in this study...
May 1, 2017: Somatosensory & Motor Research
https://www.readbyqxmd.com/read/28420732/modulation-of-tmem16a-channel-activity-by-the-von-willebrand-factor-type-a-vwa-domain-of-the-calcium-activated-chloride-channel-regulator-1-clca1
#7
Monica Sala-Rabanal, Zeynep Yurtsever, Kayla N Berry, Colin G Nichols, Tom J Brett
Calcium-activated chloride channels (CaCCs) are key players in transepithelial ion transport and fluid secretion, smooth muscle constriction, neuronal excitability, and cell proliferation. The CaCC regulator 1 (CLCA1) modulates the activity of the CaCC TMEM16A/Anoctamin 1 (ANO1) by directly engaging the channel at the cell surface, but the exact mechanism is unknown. Here, we demonstrate that the von Willebrand factor type A (VWA) domain within the cleaved CLCA1 N-terminal fragment is necessary and sufficient for this interaction...
April 18, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28412580/a-non-toxic-dose-of-cobalt-chloride-blocks-hair-cells-of-the-zebrafish-lateral-line
#8
William J Stewart, Jacob L Johansen, James C Liao
Experiments on the flow-sensitive lateral line system of fishes have provided important insights into the function and sensory transduction of vertebrate hair cells. A common experimental approach has been to pharmacologically block lateral line hair cells and measure how behavior changes. Cobalt chloride (CoCl2) blocks the lateral line by inhibiting calcium movement through the membrane channels of hair cells, but high concentrations can be toxic, making it unclear whether changes in behavior are due to a blocked lateral line or poor health...
April 12, 2017: Hearing Research
https://www.readbyqxmd.com/read/28398517/depolarization-causes-the-formation-of-a-ternary-complex-between-glialcam-mlc1-and-clc-2-in-astrocytes-implications-in-megalencephalic-leukoencephalopathy
#9
Sònia Sirisi, Xabier Elorza-Vidal, Tanit Arnedo, Mercedes Armand-Ugón, Gerard Callejo, Xavier Capdevila-Nortes, Tania López-Hernández, Uwe Schulte, Alejandro Barrallo-Gimeno, Virginia Nunes, Xavier Gasull, Raúl Estévez
Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare type of leukodystrophy caused by mutations in either MLC1 or GLIALCAM. GlialCAM is necessary for the correct targeting of MLC1, but also for the targeting of the Cl- channel ClC-2. Furthermore, GlialCAM modifies ClC-2 functional properties in vitro. However, in vivo studies in GlialCAM-/- mice have shown that the modification of ClC-2 activity only occurs in oligodendrocytes, despite GlialCAM and ClC-2 being expressed in astrocytes. Thus, the relationship between GlialCAM, MLC1 and ClC-2 in astrocytes is unknown...
April 7, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28374007/contribution-of-resting-conductance-gabaa-receptor-mediated-miniature-synaptic-currents-and-neurosteroid-to-chloride-homeostasis-in-central-neurons
#10
Tushar D Yelhekar, Michael Druzin, Staffan Johansson
Maintenance of a low intraneuronal Cl(-) concentration, [Cl(-)]i, is critical for inhibition in the CNS. Here, the contribution of passive, conductive Cl(-) flux to recovery of [Cl(-)]i after a high load was analyzed in mature central neurons from rat. A novel method for quantifying the resting Cl(-) conductance, important for [Cl(-)]i recovery, was developed and the possible contribution of GABAA and glycine receptors and of ClC-2 channels to this conductance was analyzed. The hypothesis that spontaneous, action potential-independent release of GABA is important for [Cl(-)]i recovery was tested...
March 2017: ENeuro
https://www.readbyqxmd.com/read/28344592/dysbindin-deficiency-modifies-the-expression-of-gaba-neuron-and-ion-permeation-transcripts-in-the-developing-hippocampus
#11
Jennifer Larimore, Stephanie A Zlatic, Miranda Arnold, Kaela S Singleton, Rebecca Cross, Hannah Rudolph, Martha V Bruegge, Andrea Sweetman, Cecilia Garza, Eli Whisnant, Victor Faundez
The neurodevelopmental factor dysbindin is required for synapse function and GABA interneuron development. Dysbindin protein levels are reduced in the hippocampus of schizophrenia patients. Mouse dysbindin genetic defects and other mouse models of neurodevelopmental disorders share defective GABAergic neurotransmission and, in several instances, a loss of parvalbumin-positive interneuron phenotypes. This suggests that mechanisms downstream of dysbindin deficiency, such as those affecting GABA interneurons, could inform pathways contributing to or ameliorating diverse neurodevelopmental disorders...
2017: Frontiers in Genetics
https://www.readbyqxmd.com/read/28301408/k-cl-cotransporter-2-mediated-cl-extrusion-determines-developmental-stage-dependent-impact-of-propofol-anesthesia-on-dendritic-spines
#12
Martin Puskarjov, Hubert Fiumelli, Adrian Briner, Timea Bodogan, Kornel Demeter, Claudia-Marvine Lacoh, Martina Mavrovic, Peter Blaesse, Kai Kaila, Laszlo Vutskits
BACKGROUND: General anesthetics potentiating γ-aminobutyric acid (GABA)-mediated signaling are known to induce a persistent decrement in excitatory synapse number in the cerebral cortex when applied during early postnatal development, while an opposite action is produced at later stages. Here, the authors test the hypothesis that the effect of general anesthetics on synaptogenesis depends upon the efficacy of GABA receptor type A (GABAA)-mediated inhibition controlled by the developmental up-regulation of the potassium-chloride (K-Cl) cotransporter 2 (KCC2)...
May 2017: Anesthesiology
https://www.readbyqxmd.com/read/28289711/the-volume-regulated-anion-channel-lrrc8-in-nodose-neurons-is-sensitive-to-acidic-ph
#13
Runping Wang, Yongjun Lu, Susheel Gunasekar, Yanhui Zhang, Christopher J Benson, Mark W Chapleau, Rajan Sah, François M Abboud
The leucine rich repeat containing protein 8A (LRRC8A), or SWELL1, is an essential component of the volume-regulated anion channel (VRAC) that is activated by cell swelling and ionic strength. We report here for the first time to our knowledge its expression in a primary cell culture of nodose ganglia neurons and its localization in the soma, neurites, and neuronal membrane. We show that this neuronal VRAC/SWELL1 senses low external pH (pHo) in addition to hypoosmolarity. A robust sustained chloride current is seen in 77% of isolated nodose neurons following brief exposures to extracellular acid pH...
March 9, 2017: JCI Insight
https://www.readbyqxmd.com/read/28264060/whole-exome-sequencing-implicates-eye-development-the-unfolded-protein-response-and-plasma-membrane-homeostasis-in-primary-open-angle-glaucoma
#14
Tiger Zhou, Emmanuelle Souzeau, Shiwani Sharma, John Landers, Richard Mills, Ivan Goldberg, Paul R Healey, Stuart Graham, Alex W Hewitt, David A Mackey, Anna Galanopoulos, Robert J Casson, Jonathan B Ruddle, Jonathan Ellis, Paul Leo, Matthew A Brown, Stuart MacGregor, David J Lynn, Kathryn P Burdon, Jamie E Craig
PURPOSE: To identify biological processes associated with POAG and its subtypes, high-tension (HTG) and normal-tension glaucoma (NTG), by analyzing rare potentially damaging genetic variants. METHODS: A total of 122 and 65 unrelated HTG and NTG participants, respectively, with early onset advanced POAG, 103 non-glaucoma controls and 993 unscreened ethnicity-matched controls were included in this study. Study participants without myocilin disease-causing variants and non-glaucoma controls were subjected to whole exome sequencing on an Illumina HiSeq2000...
2017: PloS One
https://www.readbyqxmd.com/read/28256198/calcium-activated-chloride-channels-a-new-target-to-control-the-spiking-pattern-of-neurons
#15
EDITORIAL
Go Eun Ha, Eunji Cheong
The nature of encoded information in neural circuits is determined by neuronal firing patterns and frequencies. This paper discusses the molecular identity and cellular mechanisms of spike-frequency adaptation in the central nervous system (CNS). Spike-frequency adaptation in thalamocortical (TC) and CA1 hippocampal neurons is mediated by the Ca2(+)-activated Cl(-) channel (CACC) anoctamin-2 (ANO2). Knockdown of ANO2 in these neurons results in increased number of spikes, in conjunction with significantly reduced spike-frequency adaptation...
March 2017: BMB Reports
https://www.readbyqxmd.com/read/28255969/-optogenetics-a-therapeutic-option-for-advanced-retinal-dystrophies
#16
A Swiersy, S D Klapper, V Busskamp
Optogenetics refers to the genetic modification of cells to express light-sensitive proteins, which mediate ion flow or secondary signalling cascades upon light exposure. Channelrhodopsin, the most famous example, is an unselective cation channel, which opens when exposed to blue light, thus mediating the depolarisation of the expressing cell. Along with other light-sensitive proteins such as the chloride pump eNpHR, which mediates light-activated hyperpolarisation, the optogenetic toolset offers a wide range of non-invasive single cell manipulations...
March 2017: Klinische Monatsblätter Für Augenheilkunde
https://www.readbyqxmd.com/read/28198817/dynamic-properties-of-calcium-activated-chloride-currents-in-xenopus-laevis-oocytes
#17
Ildefonso M De la Fuente, Iker Malaina, Alberto Pérez-Samartín, María Dolores Boyano, Gorka Pérez-Yarza, Carlos Bringas, Álvaro Villarroel, María Fedetz, Rogelio Arellano, Jesus M Cortes, Luis Martínez
Chloride is the most abundant permeable anion in the cell, and numerous studies in the last two decades highlight the great importance and broad physiological role of chloride currents mediated anion transport. They participate in a multiplicity of key processes, as for instance, the regulation of electrical excitability, apoptosis, cell cycle, epithelial secretion and neuronal excitability. In addition, dysfunction of Cl(-) channels is involved in a variety of human diseases such as epilepsy, osteoporosis and different cancer types...
February 13, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28110691/is-insulin-growth-factor-1-the-future-for-treating-autism-spectrum-disorder-and-or-schizophrenia
#18
Rami Bou Khalil
To date, no curative psychopharmacologic treatment exists for the core symptoms of autism spectrum disorder (ASD) as well as for schizophrenia. Bumatenide is a specific antagonist of the first isoform of the Na-K-Cl cotransporter (NKCC1). It is usually used as a diuretic but may also promote a decrease in intraneuronal chloride ion concentration leading to hyperpolarization in neuronal membrane and subsequent decrease in neuronal hyperexcitability. This physiologic effect has been considered to be behind the relative efficacy of bumetanide in improving symptoms of ASD and, to a lesser extent, schizophrenia...
February 2017: Medical Hypotheses
https://www.readbyqxmd.com/read/28093304/chloride-conducting-light-activated-channel-gtacr2-can-produce-both-cessation-of-firing-and-generation-of-action-potentials-in-cortical-neurons-in-response-to-light
#19
A Y Malyshev, M V Roshchin, G R Smirnova, D A Dolgikh, P M Balaban, M A Ostrovsky
Optogenetics is a powerful technique in neuroscience that provided a great success in studying the brain functions during the last decade. Progress of optogenetics crucially depends on development of new molecular tools. Light-activated cation-conducting channelrhodopsin2 was widely used for excitation of cells since the emergence of optogenetics. In 2015 a family of natural light activated chloride channels GtACR was identified which appeared to be a very promising tool for using in optogenetics experiments as a cell silencer...
January 16, 2017: Neuroscience Letters
https://www.readbyqxmd.com/read/28053034/simultaneous-loss-of-nckx4-and-cng-channel-desensitization-impairs-olfactory-sensitivity
#20
Christopher H Ferguson, Haiqing Zhao
In vertebrate olfactory sensory neurons (OSNs), Ca(2+) plays key roles in both mediating and regulating the olfactory response. Ca(2+) enters OSN cilia during the response through the olfactory cyclic nucleotide-gated (CNG) channel and stimulates a depolarizing chloride current by opening the olfactory Ca(2+)-activated chloride channel to amplify the response. Ca(2+) also exerts negative regulation on the olfactory transduction cascade, through mechanisms that include reducing the CNG current by desensitizing the CNG channel via Ca(2+)/calmodulin (CaM), to reduce the response...
January 4, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
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