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https://www.readbyqxmd.com/read/28472657/structural-bases-of-desensitization-in-ampa-receptor-auxiliary-subunit-complexes
#1
Edward C Twomey, Maria V Yelshanskaya, Robert A Grassucci, Joachim Frank, Alexander I Sobolevsky
Fast excitatory neurotransmission is mediated by AMPA-subtype ionotropic glutamate receptors (AMPARs). AMPARs, localized at post-synaptic densities, are regulated by transmembrane auxiliary subunits that modulate AMPAR assembly, trafficking, gating, and pharmacology. Aberrancies in AMPAR-mediated signaling are associated with numerous neurological disorders. Here, we report cryo-EM structures of an AMPAR in complex with the auxiliary subunit GSG1L in the closed and desensitized states. GSG1L favors the AMPAR desensitized state, where channel closure is facilitated by profound structural rearrangements in the AMPAR extracellular domain, with ligand-binding domain dimers losing their local 2-fold rotational symmetry...
May 3, 2017: Neuron
https://www.readbyqxmd.com/read/28383518/genetic-architecture-of-bone-quality-variation-in-layer-chickens-revealed-by-a-genome-wide-association-study
#2
Jun Guo, Congjiao Sun, Liang Qu, Manman Shen, Taocun Dou, Meng Ma, Kehua Wang, Ning Yang
Skeletal problems in layer chickens are gaining attention due to animal welfare and economic losses in the egg industry. The genetic improvement of bone traits has been proposed as a potential solution to these issues; however, genetic architecture is not well understood. We conducted a genome-wide association study (GWAS) on bone quality using a sample of 1534 hens genotyped with a 600 K Chicken Genotyping Array. Using a linear mixed model approach, a novel locus close to GSG1L, associated with femur bone mineral density (BMD), was uncovered in this study...
April 6, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28358902/screening-for-ampa-receptor-auxiliary-subunit-specific-modulators
#3
Caleigh M Azumaya, Emily L Days, Paige N Vinson, Shaun Stauffer, Gary Sulikowski, C David Weaver, Terunaga Nakagawa
AMPA receptors (AMPAR) are ligand gated ion channels critical for synaptic transmission and plasticity. Their dysfunction is implicated in a variety of psychiatric and neurological diseases ranging from major depressive disorder to amyotrophic lateral sclerosis. Attempting to potentiate or depress AMPAR activity is an inherently difficult balancing act between effective treatments and debilitating side effects. A newly explored strategy to target subsets of AMPARs in the central nervous system is to identify compounds that affect specific AMPAR-auxiliary subunit complexes...
2017: PloS One
https://www.readbyqxmd.com/read/28257124/hyper-methylated-loci-persisting-from-sessile-serrated-polyps-to-serrated-cancers
#4
Angeline S Andrew, John A Baron, Lynn F Butterly, Arief A Suriawinata, Gregory J Tsongalis, Christina M Robinson, Christopher I Amos
Although serrated polyps were historically considered to pose little risk, it is now understood that progression down the serrated pathway could account for as many as 15%-35% of colorectal cancers. The sessile serrated adenoma/polyp (SSA/P) is the most prevalent pre-invasive serrated lesion. Our objective was to identify the CpG loci that are persistently hyper-methylated during serrated carcinogenesis, from the early SSA/P lesion through the later cancer phases of neoplasia development. We queried the loci hyper-methylated in serrated cancers within our rightsided SSA/Ps from the New Hampshire Colonoscopy Registry, using the Illumina Infinium Human Methylation 450 k panel to comprehensively assess the DNA methylation status...
March 2, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28219790/subunit-specific-synaptic-delivery-of-ampa-receptors-by-auxiliary-chaperone-proteins-tarp%C3%AE-8-and-gsg1l-in-classical-conditioning
#5
Joyce Keifer, Neeraj K Tiwari, Leah Buse, Zhaoqing Zheng
AMPA receptor (AMPAR) trafficking has emerged as a fundamental concept for understanding mechanisms of learning and memory as well as many neurological disorders. Classical conditioning is a simple and highly conserved form of associative learning. Our studies use an ex vivo brainstem preparation in which to study cellular mechanisms underlying learning during a neural correlate of eyeblink conditioning. Two stages of AMPAR synaptic delivery underlie conditioning utilizing sequential trafficking of GluA1-containing AMPARs early in conditioning followed by replacement with GluA4 subunits later...
April 3, 2017: Neuroscience Letters
https://www.readbyqxmd.com/read/27707810/gsg1l-regulates-the-strength-of-ampa-receptor-mediated-synaptic-transmission-but-not-ampa-receptor-kinetics-in-hippocampal-dentate-granule-neurons
#6
Xia Mao, Xinglong Gu, Wei Lu
GSG1L is an AMPA receptor (AMPAR) auxiliary subunit that regulates AMPAR trafficking and function in hippocampal CA1 pyramidal neurons. However, its physiological roles in other types of neurons remain to be characterized. Here, we investigated the role of GSG1L in hippocampal dentate granule cells and found that GSG1L is important for the regulation of synaptic strength but is not critical for the modulation of AMPAR deactivation and desensitization kinetics. These data demonstrate a neuronal type-specific role of GSG1L and suggest that physiological function of AMPAR auxiliary subunits may vary in different types of neurons...
January 1, 2017: Journal of Neurophysiology
https://www.readbyqxmd.com/read/27010727/genome-wide-pharmacogenomic-study-on-methadone-maintenance-treatment-identifies-snp-rs17180299-and-multiple-haplotypes-on-cyp2b6-spon1-and-gsg1l-associated-with-plasma-concentrations-of-methadone-r-and-s-enantiomers-in-heroin-dependent-patients
#7
Hsin-Chou Yang, Shih-Kai Chu, Chieh-Liang Huang, Hsiang-Wei Kuo, Sheng-Chang Wang, Sheng-Wen Liu, Ing-Kang Ho, Yu-Li Liu
Methadone maintenance treatment (MMT) is commonly used for controlling opioid dependence, preventing withdrawal symptoms, and improving the quality of life of heroin-dependent patients. A steady-state plasma concentration of methadone enantiomers, a measure of methadone metabolism, is an index of treatment response and efficacy of MMT. Although the methadone metabolism pathway has been partially revealed, no genome-wide pharmacogenomic study has been performed to identify genetic determinants and characterize genetic mechanisms for the plasma concentrations of methadone R- and S-enantiomers...
March 2016: PLoS Genetics
https://www.readbyqxmd.com/read/26932439/gsg1l-suppresses-ampa-receptor-mediated-synaptic-transmission-and-uniquely-modulates-ampa-receptor-kinetics-in-hippocampal-neurons
#8
Xinglong Gu, Xia Mao, Marc P Lussier, Mary Anne Hutchison, Liang Zhou, F Kent Hamra, Katherine W Roche, Wei Lu
Regulation of AMPA receptor (AMPAR)-mediated synaptic transmission is a key mechanism for synaptic plasticity. In the brain, AMPARs assemble with a number of auxiliary subunits, including TARPs, CNIHs and CKAMP44, which are important for AMPAR forward trafficking to synapses. Here we report that the membrane protein GSG1L negatively regulates AMPAR-mediated synaptic transmission. Overexpression of GSG1L strongly suppresses, and GSG1L knockout (KO) enhances, AMPAR-mediated synaptic transmission. GSG1L-dependent regulation of AMPAR synaptic transmission relies on the first extracellular loop domain and its carboxyl-terminus...
March 2, 2016: Nature Communications
https://www.readbyqxmd.com/read/26909693/creative-activities-in-music-a-genome-wide-linkage-analysis
#9
Jaana Oikkonen, Tuire Kuusi, Petri Peltonen, Pirre Raijas, Liisa Ukkola-Vuoti, Kai Karma, Päivi Onkamo, Irma Järvelä
Creative activities in music represent a complex cognitive function of the human brain, whose biological basis is largely unknown. In order to elucidate the biological background of creative activities in music we performed genome-wide linkage and linkage disequilibrium (LD) scans in musically experienced individuals characterised for self-reported composing, arranging and non-music related creativity. The participants consisted of 474 individuals from 79 families, and 103 sporadic individuals. We found promising evidence for linkage at 16p12...
2016: PloS One
https://www.readbyqxmd.com/read/26658868/auxiliary-subunit-gsg1l-acts-to-suppress-calcium-permeable-ampa-receptor-function
#10
Thomas P McGee, Cécile Bats, Mark Farrant, Stuart G Cull-Candy
UNLABELLED: AMPA-type glutamate receptors are ligand-gated cation channels responsible for a majority of the fast excitatory synaptic transmission in the brain. Their behavior and calcium permeability depends critically on their subunit composition and the identity of associated auxiliary proteins. Calcium-permeable AMPA receptors (CP-AMPARs) contribute to various forms of synaptic plasticity, and their dysfunction underlies a number of serious neurological conditions. For CP-AMPARs, the prototypical transmembrane AMPAR regulatory protein stargazin, which acts as an auxiliary subunit, enhances receptor function by increasing single-channel conductance, slowing channel gating, increasing calcium permeability, and relieving the voltage-dependent block by endogenous intracellular polyamines...
December 9, 2015: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/25110960/auxiliary-subunits-shepherding-ampa-receptors-to-the-plasma-membrane
#11
REVIEW
Simon C Haering, Daniel Tapken, Steffen Pahl, Michael Hollmann
Ionotropic glutamate receptors (iGluRs) are tetrameric ligand-gated cation channels that mediate excitatory signal transmission in the central nervous system (CNS) of vertebrates. The members of the iGluR subfamily of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors (AMPARs) mediate most of the fast excitatory signal transmission, and their abundance in the postsynaptic membrane is a major determinant of the strength of excitatory synapses. Therefore, regulation of AMPAR trafficking to the postsynaptic membrane is an important constituent of mechanisms involved in learning and memory formation, such as long-term potentiation (LTP) and long-term depression (LTD)...
2014: Membranes
https://www.readbyqxmd.com/read/22813734/differences-in-ampa-and-kainate-receptor-interactomes-facilitate-identification-of-ampa-receptor-auxiliary-subunit-gsg1l
#12
Natalie F Shanks, Jeffrey N Savas, Tomohiko Maruo, Ondrej Cais, Atsushi Hirao, Souichi Oe, Anirvan Ghosh, Yasuko Noda, Ingo H Greger, John R Yates, Terunaga Nakagawa
AMPA receptor (AMPA-R) complexes consist of channel-forming subunits, GluA1-4, and auxiliary proteins, including TARPs, CNIHs, synDIG1, and CKAMP44, which can modulate AMPA-R function in specific ways. The combinatorial effects of four GluA subunits binding to various auxiliary subunits amplify the functional diversity of AMPA-Rs. The significance and magnitude of molecular diversity, however, remain elusive. To gain insight into the molecular complexity of AMPA and kainate receptors, we compared the proteins that copurify with each receptor type in the rat brain...
June 28, 2012: Cell Reports
https://www.readbyqxmd.com/read/22127497/genome-wide-association-and-fine-mapping-of-genetic-loci-predisposing-to-colon-carcinogenesis-in-mice
#13
Pengyuan Liu, Yan Lu, Hongbo Liu, Weidong Wen, Dongmei Jia, Yian Wang, Ming You
To identify the genetic determinants of colon tumorigenesis, 268 male mice from 33 inbred strains derived from different genealogies were treated with azoxymethane (AOM; 10 mg/kg) once a week for six weeks to induce colon tumors. Tumors were localized exclusively within the distal colon in each of the strains examined. Inbred mouse strains exhibit a large variability in genetic susceptibility to AOM-induced colon tumorigenesis. The mean colon tumor multiplicity ranged from 0 to 38.6 (mean = 6.5 ± 8.6) and tumor volume ranged from 0 to 706...
January 2012: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/20089533/transcriptional-changes-in-huntington-disease-identified-using-genome-wide-expression-profiling-and-cross-platform-analysis
#14
Kristina Becanovic, Mahmoud A Pouladi, Raymond S Lim, Alexandre Kuhn, Paul Pavlidis, Ruth Luthi-Carter, Michael R Hayden, Blair R Leavitt
Evaluation of transcriptional changes in the striatum may be an effective approach to understanding the natural history of changes in expression contributing to the pathogenesis of Huntington disease (HD). We have performed genome-wide expression profiling of the YAC128 transgenic mouse model of HD at 12 and 24 months of age using two platforms in parallel: Affymetrix and Illumina. The data from these two powerful platforms were integrated to create a combined rank list, thereby revealing the identity of additional genes that proved to be differentially expressed between YAC128 and control mice...
April 15, 2010: Human Molecular Genetics
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