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Pengcheng Zhang, Randy Schekman
In addition to its role in forming vesicles from the endoplasmic reticulum (ER), the coat protein complex II (COPII) is also responsible for selecting specific cargo proteins to be packaged into COPII transport vesicles. Comparison of COPII vesicle formation in mammalian systems and in yeast suggested that the former uses more elaborate mechanisms for cargo recognition, presumably to cope with a significantly expanded repertoire of cargo that transits the secretory pathway. Using proTGFα, the transmembrane precursor of transforming growth factor α (TGFα), as a model cargo protein, we demonstrate in cell-free assays that at least one auxiliary cytosolic factor is specifically required for the efficient packaging of proTGFα into COPII vesicles...
June 15, 2016: Molecular Biology of the Cell
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
Nadine Erlenhardt, Hong Yu, Kavitha Abiraman, Tokiwa Yamasaki, Jacques I Wadiche, Susumu Tomita, David S Bredt
AMPA receptor (AMPAR) complexes contain auxiliary subunits that modulate receptor trafficking and gating. In addition to the transmembrane AMPAR regulatory proteins (TARPs) and cornichons (CNIH-2/3), recent proteomic studies identified a diverse array of additional AMPAR-associated transmembrane and secreted partners. We systematically surveyed these and found that PORCN and ABHD6 increase GluA1 levels in transfected cells. Knockdown of PORCN in rat hippocampal neurons, which express it in high amounts, selectively reduces levels of all tested AMPAR complex components...
February 2, 2016: Cell Reports
Hirotaka Matsuo, Ken Yamamoto, Hirofumi Nakaoka, Akiyoshi Nakayama, Masayuki Sakiyama, Toshinori Chiba, Atsushi Takahashi, Takahiro Nakamura, Hiroshi Nakashima, Yuzo Takada, Inaho Danjoh, Seiko Shimizu, Junko Abe, Yusuke Kawamura, Sho Terashige, Hiraku Ogata, Seishiro Tatsukawa, Guang Yin, Rieko Okada, Emi Morita, Mariko Naito, Atsumi Tokumasu, Hiroyuki Onoue, Keiichi Iwaya, Toshimitsu Ito, Tappei Takada, Katsuhisa Inoue, Yukio Kato, Yukio Nakamura, Yutaka Sakurai, Hiroshi Suzuki, Yoshikatsu Kanai, Tatsuo Hosoya, Nobuyuki Hamajima, Ituro Inoue, Michiaki Kubo, Kimiyoshi Ichida, Hiroshi Ooyama, Toru Shimizu, Nariyoshi Shinomiya
OBJECTIVE: Gout, caused by hyperuricaemia, is a multifactorial disease. Although genome-wide association studies (GWASs) of gout have been reported, they included self-reported gout cases in which clinical information was insufficient. Therefore, the relationship between genetic variation and clinical subtypes of gout remains unclear. Here, we first performed a GWAS of clinically defined gout cases only. METHODS: A GWAS was conducted with 945 patients with clinically defined gout and 1213 controls in a Japanese male population, followed by replication study of 1048 clinically defined cases and 1334 controls...
April 2016: Annals of the Rheumatic Diseases
Natalie F Shanks, Ondrej Cais, Tomohiko Maruo, Jeffrey N Savas, Elena I Zaika, Caleigh M Azumaya, John R Yates, Ingo Greger, Terunaga Nakagawa
Cornichon homologs (CNIHs) are AMPA-type glutamate receptor (AMPAR) auxiliary subunits that modulate AMPAR ion channel function and trafficking. Mechanisms underlying this interaction and functional modulation of the receptor complex are currently unclear. Here, using proteins expressed from mouse and rat cDNA, we show that CNIH-3 forms a stable complex with tetrameric AMPARs and contributes to the transmembrane density in single-particle electron microscopy structures. Peptide array-based screening and in vitro mutagenesis identified two clusters of conserved membrane-proximal residues in CNIHs that contribute to AMPAR binding...
September 3, 2014: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
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
Chun-Wei Tung, Ming-Tsang Wu, Yu-Kuei Chen, Chun-Chieh Wu, Wei-Chung Chen, Hsien-Pin Li, Shah-Hwa Chou, Deng-Chyang Wu, I-Chen Wu
Esophageal squamous cell cancer (ESCC) is one of the most common fatal human cancers. The identification of biomarkers for early detection could be a promising strategy to decrease mortality. Previous studies utilized microarray techniques to identify more than one hundred genes; however, it is desirable to identify a small set of biomarkers for clinical use. This study proposes a sequential forward feature selection algorithm to design decision tree models for discriminating ESCC from normal tissues. Two potential biomarkers of RUVBL1 and CNIH were identified and validated based on two public available microarray datasets...
2013: TheScientificWorldJournal
Bruce E Herring, Yun Shi, Young Ho Suh, Chan-Ying Zheng, Sabine M Blankenship, Katherine W Roche, Roger A Nicoll
Cornichon-2 and cornichon-3 (CNIH-2/-3) are AMPA receptor (AMPAR) binding proteins that promote receptor trafficking and markedly slow AMPAR deactivation in heterologous cells, but their role in neurons is unclear. Using CNIH-2 and CNIH-3 conditional knockout mice, we find a profound reduction of AMPAR synaptic transmission in the hippocampus. This deficit is due to the selective loss of surface GluA1-containing AMPARs (GluA1A2 heteromers), leaving a small residual pool of synaptic GluA2A3 heteromers. The kinetics of AMPARs in neurons lacking CNIH-2/-3 are faster than those in WT neurons due to the fast kinetics of GluA2A3 heteromers...
March 20, 2013: Neuron
Akio Sumioka
Glutamate is a major excitatory neurotransmitter in the vertebrate brain. Among the ionotropic glutamate receptors, α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) glutamate receptors are the major receptors mediating excitatory fast synaptic transmission. AMPA receptors are also responsible for modifying synaptic strength through the regulation of their numbers at synapses. Their high regulatability, therefore, could contribute to the mechanisms of synaptic plasticity. The mechanisms regulating AMPA receptor trafficking have evoked great interest through the decades...
April 2013: Journal of Biochemistry
Veronika Mauric, Andrea Mölders, Nadine Harmel, Bernd Heimrich, Olga A Sergeeva, Nikolaj Klöcker
Besides mediating most of the fast excitatory neurotransmission in the mammalian CNS, ionotropic glutamate receptors of the AMPA subtype (AMPARs) serve highly diverse functions in brain development controlling neuronal migration, synaptic growth, and synaptic maturation. Pioneering proteomic studies suggest that this functional diversity is met by a great molecular complexity in native AMPAR composition. Here, we have investigated the expression patterns of two recently identified AMPAR constituents, the cornichon homologues CNIH-2 and CNIH-3, and their assembly with the AMPAR core subunits GluA1-4 in developing rat brain...
September 2013: Molecular and Cellular Neurosciences
Jana B Drummond, Micah Simmons, Vahram Haroutunian, James H Meador-Woodruff
Schizophrenia has been proposed to be associated with abnormal glutamatergic neurotransmission. The AMPA subtype of glutamate receptors (AMPARs) mediates fast excitatory synaptic transmission in the brain, and their trafficking and function is regulated in part by AMPAR auxiliary proteins including the cornichons (CNIH) and transmembrane AMPAR-regulatory proteins. Abnormal regulation of AMPARs through altered expression of these auxiliary proteins could induce changes in glutamatergic neurotransmission and thus the pathophysiology of schizophrenia...
December 5, 2012: Neuroreport
Ian D Coombs, David Soto, Marzieh Zonouzi, Massimiliano Renzi, Chris Shelley, Mark Farrant, Stuart G Cull-Candy
Ionotropic glutamate receptors, which underlie a majority of excitatory synaptic transmission in the CNS, associate with transmembrane proteins that modify their intracellular trafficking and channel gating. Significant advances have been made in our understanding of AMPA-type glutamate receptor (AMPAR) regulation by transmembrane AMPAR regulatory proteins. Less is known about the functional influence of cornichons-unrelated AMPAR-interacting proteins, identified by proteomic analysis. Here we confirm that cornichon homologs 2 and 3 (CNIH-2 and CNIH-3), but not CNIH-1, slow the deactivation and desensitization of both GluA2-containing calcium-impermeable and GluA2-lacking calcium-permeable (CP) AMPARs expressed in tsA201 cells...
July 18, 2012: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
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
Nadine Harmel, Barbara Cokic, Gerd Zolles, Henrike Berkefeld, Veronika Mauric, Bernd Fakler, Valentin Stein, Nikolaj Klöcker
Fast excitatory neurotransmission in the mammalian central nervous system is mainly mediated by ionotropic glutamate receptors of the AMPA subtype (AMPARs). AMPARs are protein complexes of the pore-lining α-subunits GluA1-4 and auxiliary β-subunits modulating their trafficking and gating. By a proteomic approach, two homologues of the cargo exporter cornichon, CNIH-2 and CNIH-3, have recently been identified as constituents of native AMPARs in mammalian brain. In heterologous reconstitution experiments, CNIH-2 promotes surface expression of GluAs and modulates their biophysical properties...
2012: PloS One
Martin B Gill, Akihiko S Kato, He Wang, David S Bredt
Transmembrane AMPA receptor regulatory proteins (TARPs) are auxiliary subunits that modulate AMPA receptor trafficking, gating and pharmacology throughout the brain. Why cornichon-2 (CNIH-2), another AMPA receptor-associated protein, modulates AMPA receptor gating and pharmacology in hippocampal neurons but not cerebellar granule neurons remains unresolved. Here, we report that CNIH-2 differentially impacts Type-Ia (γ-2 or γ-3) vs. Type-Ib (γ-4 or γ-8) TARP-containing AMPA receptors. Specifically, with AMPA receptors comprising γ-2, the cerebellar-enriched TARP isoform, CNIH-2 decreases I(KA) /I(Glu) ratio and decreases cyclothiazide efficacy while having minimal impact on recovery from desensitization and deactivation kinetics...
January 2012: European Journal of Neuroscience
Christoph Straub, Susumu Tomita
At excitatory synapses in the brain, glutamate released from nerve terminals binds to glutamate receptors to mediate signaling between neurons. Glutamate receptors expressed in heterologous cells show ion channel activity. Recently, native glutamate receptors were shown to contain auxiliary subunits that modulate the trafficking and/or channel properties. The AMPA receptor (AMPAR) can contain TARP and CNIHs as the auxiliary subunits, whereas kainate receptor (KAR) can contain the Neto auxiliary subunit. Each of these auxiliary subunits uniquely modulates the glutamate receptors, and determines properties of native glutamate receptors...
June 2012: Current Opinion in Neurobiology
Martin B Gill, Akihiko S Kato, Matthew F Roberts, Hong Yu, He Wang, Susumu Tomita, David S Bredt
Neuronal AMPA receptor complexes comprise a tetramer of GluA pore-forming subunits as well as accessory components, including transmembrane AMPA receptor regulatory proteins (TARPs) and cornichon-2/3 (CNIH-2/3). The mechanisms that control AMPA receptor complex assembly remain unclear. AMPA receptor responses in neurons differ from those in cell lines transfected with GluA plus TARPs γ-8 or γ-7, which show unusual resensitization kinetics and non-native AMPA receptor pharmacologies. Using tandem GluA/TARP constructs to constrain stoichiometry, we show here that these peculiar kinetic and pharmacological signatures occur in channels with four TARP subunits per complex...
May 4, 2011: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Douglas A Schober, Martin B Gill, Hong Yu, Douglas L Gernert, Matthew W Jeffries, Paul L Ornstein, Akihiko S Kato, Christian C Felder, David S Bredt
AMPA receptors mediate fast excitatory transmission in the brain. Neuronal AMPA receptors comprise GluA pore-forming principal subunits and can associate with multiple modulatory components, including transmembrane AMPA receptor regulatory proteins (TARPs) and CNIHs (cornichons). AMPA receptor potentiators and non-competitive antagonists represent potential targets for a variety of neuropsychiatric disorders. Previous studies showed that the AMPA receptor antagonist GYKI-53655 displaces binding of a potentiator from brain receptors but not from recombinant GluA subunits...
April 15, 2011: Journal of Biological Chemistry
Akihiko S Kato, Martin B Gill, Michelle T Ho, Hong Yu, Yuan Tu, Edward R Siuda, He Wang, Yue-Wei Qian, Eric S Nisenbaum, Susumu Tomita, David S Bredt
Transmembrane AMPA receptor regulatory proteins (TARPs) and cornichon proteins (CNIH-2/3) independently modulate AMPA receptor trafficking and gating. However, the potential for interactions of these subunits within an AMPA receptor complex is unknown. Here, we find that TARPs γ-4, γ-7, and γ-8, but not γ-2, γ-3, or γ-5, cause AMPA receptors to "resensitize" upon continued glutamate application. With γ-8, resensitization occurs with all GluA subunit combinations; however, γ-8-containing hippocampal neurons do not display resensitization...
December 22, 2010: Neuron
Carolina Perez Castro, Denise Piscopo, Takatoshi Nakagawa, Rik Derynck
Cornichon proteins are structurally related transmembrane proteins that have been studied in and Drosophila and yeast. In Drosophila, Cornichon (Cni) is involved in embryo polarization by the TGFalpha-related Gurken. In yeast, the Cni-related Erv14 is required for axial budding. A cargo receptor function has been proposed for Erv14 and Cni. Four mammalian Cni-like sequences have been identified. We carried out parallel functional analyses of the human Cni ortholog CNIH and Drosophila Cni in the processing and presentation of TGFalpha family proteins...
July 15, 2007: Journal of Cell Science
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