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Héctor Gaitán-Peñas, Antonella Gradogna, Lara Laparra-Cuervo, Carles Solsona, Victor Fernández-Dueñas, Alejandro Barrallo-Gimeno, Francisco Ciruela, Melike Lakadamyali, Michael Pusch, Raúl Estévez
Volume-regulated anion channels (VRACs) play an important role in controlling cell volume by opening upon cell swelling. Recent work has shown that heteromers of LRRC8A with other LRRC8 members (B, C, D, and E) form the VRAC. Here, we used Xenopus oocytes as a simple system to study LRRC8 proteins. We discovered that adding fluorescent proteins to the C-terminus resulted in constitutive anion channel activity. Using these constructs, we reproduced previous findings indicating that LRRC8 heteromers mediate anion and osmolyte flux with subunit-dependent kinetics and selectivity...
October 4, 2016: Biophysical Journal
Claudio L Morales-Perez, Colleen M Noviello, Ryan E Hibbs
Nicotinic acetylcholine receptors are ligand-gated ion channels that mediate fast chemical neurotransmission at the neuromuscular junction and have diverse signalling roles in the central nervous system. The nicotinic receptor has been a model system for cell-surface receptors, and specifically for ligand-gated ion channels, for well over a century. In addition to the receptors' prominent roles in the development of the fields of pharmacology and neurobiology, nicotinic receptors are important therapeutic targets for neuromuscular disease, addiction, epilepsy and for neuromuscular blocking agents used during surgery...
October 3, 2016: Nature
Raphael Jorand, Sunetra Biswas, Devin L Wakefield, Steven J Tobin, Ottavia Golfetto, Kelsey Hilton, Michelle Ko, Joe W Ramos, Alexander R Small, Peiguo Chu, Gagandeep Singh, Tijana Jovanovic-Talisman
Pancreatic ductal adenocarcinoma (PDAC), a particularly aggressive malignancy, has been linked to atypical levels, certain mutations, and aberrant signaling of G-protein coupled receptors (GPCRs). GPCRs have been challenging to target in cancer because they organize into complex networks in tumor cells. To dissect such networks with nanometer-scale precision, traditional biochemical approaches were combined herein with super-resolution microscopy methods. A novel interaction specific to PDAC was identified between mu opioid receptor (MOR) and somatostatin receptor 2 (SSTR2)...
September 28, 2016: Molecular Biology of the Cell
Hans K H Ng, Kaleeckal G Harikumar, Laurence J Miller, Billy K C Chow
The involvement of secretin (SCT) and secretin receptor (SCTR) in regulating body water homeostasis is well established. Identified as one of the vasopressin (Vp)-independent mechanisms in fluid balance, SCT regulates aquaporin 2 (AQP2) in the kidney distal collecting duct cells through activating intracellular cAMP production. This ability to bypass Vp-mediated water reabsorption in kidney implicates SCT's potential to treat nephrogenic diabetes insipidus (NDI). Research on NDI in the past has largely been focused on the searching for mutations in vasopressin receptor 2 (AVPR2), while the functional relationship between SCTR, AVPR2 and NDI remains unclear...
2016: PloS One
Abdulah El Tarazi, Yoann Lussier, Sandra Da Cal, Pierre Bissonnette, Daniel G Bichet
Aquaporin-2 (AQP2) is a homotetrameric water channel responsible for the final water reuptake in the kidney. Mutations in the protein induce nephrogenic diabetes insipidus (NDI), which challenges the water balance by producing large urinary volumes. Although recessive AQP2 mutations are believed to generate non-functional and monomeric proteins, the literature identifies several mild mutations which suggest the existence of mixed wt/mut tetramers likely to carry function in heterozygotes. Using Xenopus oocytes, we tested this hypothesis and found that mild mutants (V24A, D150E) can associate with wt-AQP2 in mixed heteromers, providing clear functional gain in the process (62 ± 17% and 63 ± 17% increases, respectively), conversely to the strong monomeric R187C mutant which fails to associate with wt-AQP2...
2016: Scientific Reports
Joshua Levitz, Chris Habrian, Shashank Bharill, Zhu Fu, Reza Vafabakhsh, Ehud Y Isacoff
G protein-coupled receptors (GPCRs) mediate cellular responses to a wide variety of extracellular stimuli. GPCR dimerization may expand signaling diversity and tune functionality, but little is known about the mechanisms of subunit assembly and interaction or the signaling properties of heteromers. Using single-molecule subunit counting on class C metabotropic glutamate receptors (mGluRs), we map dimerization determinants and define a heterodimerization profile. Intersubunit fluorescence resonance energy transfer measurements reveal that interactions between ligand-binding domains control the conformational rearrangements underlying receptor activation...
October 5, 2016: Neuron
Vidya Pawar, Axel Poulet, Gwénaëlle Détourné, Christophe Tatout, Emmanuel Vanrobays, David E Evans, Katja Graumann
This paper describes the characterisation of a new family of higher plant nuclear envelope-associated proteins (NEAPs) that interact with other proteins of the nuclear envelope. In the model plant Arabidopsis thaliana, the family consists of three genes expressed ubiquitously (AtNEAP1-3) and a pseudogene (AtNEAP4). NEAPs consist of extensive coiled-coil domains, followed by a nuclear localisation signal and a C-terminal predicted transmembrane domain. Domain deletion mutants confirm the presence of a functional nuclear localisation signal and transmembrane domain...
October 2016: Journal of Experimental Botany
Johan-Till Pougnet, Benjamin Compans, Audrey Martinez, Daniel Choquet, Eric Hosy, Eric Boué-Grabot
Plasticity at excitatory synapses can be induced either by synaptic release of glutamate or the release of gliotransmitters such as ATP. Recently, we showed that postsynaptic P2X2 receptors activated by ATP released from astrocytes downregulate synaptic AMPAR, providing a novel mechanism by which glial cells modulate synaptic activity. ATP- and lNMDA-induced depression in the CA1 region of the hippocampus are additive, suggesting distinct molecular pathways. AMPARs are homo-or hetero-tetramers composed of GluA1-A4...
2016: Scientific Reports
Alberto J Rico, Iria G Dopeso-Reyes, Eva Martínez-Pinilla, Diego Sucunza, Diego Pignataro, Elvira Roda, David Marín-Ramos, José L Labandeira-García, Susan R George, Rafael Franco, José L Lanciego
Although it has long been widely accepted that dopamine receptor types D1 and D2 form GPCR heteromers in the striatum, the presence of D1-D2 receptor heteromers has been recently challenged. In an attempt to properly characterize D1-D2 receptor heteromers, here we have used the in situ proximity ligation assay (PLA) in striatal sections comprising the caudate nucleus, the putamen and the core and shell territories of the nucleus accumbens. Experiments were carried out in control macaques as well as in MPTP-treated animals (with and without dyskinesia)...
September 9, 2016: Brain Structure & Function
Yingjun Duan, Qianxue Chen
Transforming growth factor-β (TGF-β) proteins are important cytokines in the occurrence and development of tumors. However, its neural functions in glioma are still not understood. In the present study, we evaluated the effects of TGF-β1 on glioma cell line U87. miR-205 and miR-195 were involved in TGF-β1 signaling pathway. Quantitative real-time PCR was used to detect miR-205 and miR-195 levels in human glioma tissue samples and U87 cells treated with different concentrations of TGF-β1. Enzyme-linked immunosorbent assay (ELISA) was performed to determine TGF-β1 in the glioma patients peripheral blood...
October 2016: Oncology Reports
Bruno D Cerrato, Oscar A Carretero, Brana Janic, Hernán E Grecco, Mariela M Gironacci
Bradykinin B2 receptor (B2R) and angiotensin-(1-7) Mas receptor (MasR)-mediated effects are physiologically interconnected. The molecular basis for such cross talk is unknown. It is hypothesized that the cross talk occurs at the receptor level. We investigated B2R-MasR heteromerization and the functional consequences of such interaction. B2R fused to the cyan fluorescent protein and MasR fused to the yellow fluorescent protein were transiently coexpressed in human embryonic kidney293T cells. Fluorescence resonance energy transfer analysis showed that B2R and MasR formed a constitutive heteromer, which was not modified by their agonists...
October 2016: Hypertension
Christopher J Earley, George R Uhl, Stefan Clemens, Sergi Ferré
Restless legs syndrome (RLS) is primarily treated with levodopa and dopaminergics that target the inhibitory dopamine receptor subtypes D3 and D2. The initial success of this therapy led to the idea of a hypodopaminergic state as the mechanism underlying RLS. However, multiple lines of evidence suggest that this simplified concept of a reduced dopamine function as the basis of RLS is incomplete. Moreover, long-term medication with the D2/D3 agonists leads to a reversal of the initial benefits of dopamine agonists and augmentation, which is a worsening of symptoms under therapy...
June 27, 2016: Sleep Medicine
Terrell Holloway, Jose L Moreno, Javier González-Maeso
The heteromeric receptor complex between 5-HT2A and mGlu2 has been implicated in some of the behavioral phenotypes in mouse models of psychosis(1,2). Consequently, investigation of structural details of the interaction between 5-HT2A and mGlu2 affecting schizophrenia-related behaviors represents a powerful translational tool. As previously shown, the head-twitch response (HTR) in mice is elicited by hallucinogenic drugs and this behavioral response is absent in 5-HT2A knockout (KO) mice(3,4). Additionally, by conditionally expressing the 5-HT2A receptor only in cortex, it was demonstrated that 5-HT2A receptor-dependent signaling pathways on cortical pyramidal neurons are sufficient to elicit head-twitch behavior in response to hallucinogenic drugs(3)...
2016: Journal of Visualized Experiments: JoVE
Siri Valen Egeland, Léon Reubsaet, Elisabeth Paus, Trine Grønhaug Halvorsen
If the biomarker potential of intact heteromers and their free subunits is different, differentiation between these forms may reveal important clinical information. Such differentiation may however be analytically challenging. One possible way of circumventing this challenge is by performing a dual-immuno-MS approach. In the present paper, a two-step immunoaffinity sample preparation step is succeeded by digestion and subsequent LC-MS analysis to provide high-sensitivity quantification and differentiation between the heterodimer human chorionic gonadotropin (hCG) and its free β-subunit in serum...
October 2016: Analytical and Bioanalytical Chemistry
Hae-Jin Kweon, Dong-Il Kim, Yeonju Bae, Jae-Yong Park, Byung-Chang Suh
Acid-sensing ion channels (ASICs) are proton-activated cation channels that play important roles as typical proton sensors during pathophysiological conditions and normal synaptic activities. Among the ASIC subunits, ASIC2a and ASIC2b are alternative splicing products from the same gene, ACCN1. It has been shown that ASIC2 isoforms have differential subcellular distribution: ASIC2a targets the cell surface by itself, while ASIC2b resides in the ER. However, the underlying mechanism for this differential subcellular localization remained to be further elucidated...
2016: Scientific Reports
Eyleen Corrales, Arcadi Navarro, Patricia Cuenca, Domingo Campos
Alterations in the monoaminergic neurotransmission systems are suspected to be involved in the etiology of neuropsychiatric disorders, including depression. The role of these pathways in the risk of developing depressive symptoms during childhood or adolescence is still not completely clear. This study sought to identify putative genetic factors in genes of serotonergic and dopaminergic systems modulating the level of manifestation of depressive symptoms in children and adolescents. We analyzed 170 single nucleotide polymorphisms (SNPs) in 21 candidate dopaminergic and serotonergic genes in a non-clinical sample of 410 Costa Rican participants of ages between 7 and 18 years, assessing the severity of depressive symptoms through the Child Depression Inventory (CDI)...
October 30, 2016: Psychiatry Research
Colleen M Niswender, Carrie K Jones, Xin Lin, Michael Bubser, Analisa Thompson Gray, Anna L Blobaum, Darren W Engers, Alice L Rodriguez, Matthew T Loch, J Scott Daniels, Craig W Lindsley, Corey R Hopkins, Jonathan A Javitch, P Jeffrey Conn
Metabotropic glutamate receptor 4 (mGlu4) is emerging as a potential therapeutic target for numerous central nervous system indications, including Parkinson's disease (PD). As the glutamate binding sites among the eight mGlu receptors are highly conserved, modulation of receptor activity via allosteric sites within the receptor transmembrane domains using positive and negative allosteric modulators (PAMs and NAMs, respectively) has become a common strategy. We and others have used PAMs targeting mGlu4 to show that potentiation of receptor signaling induces antiparkinsonian activity in a variety of PD animal models, including haloperidol-induced catalepsy and 6-hydroxydopamine-induced lesion...
September 21, 2016: ACS Chemical Neuroscience
Roberta Imperatore, Letizia Palomba, Giovanna Morello, Alessandro Di Spiezio, Fabiana Piscitelli, Vincenzo Di Marzo, Luigia Cristino
Orexin 1 (OX-1R) and cannabinoid receptor (CB1R) belong to the superfamily of G-protein-coupled receptors (GPCRs) and are mostly coupled to Gq and Gi/o proteins, respectively. In vitro studies in host cells over-expressing OX-1R and CB1R revealed a functional interaction between these receptors, through either their ability to form heteromers or the property for OX-1R to trigger the biosynthesis of 2-arachidonoylglycerol (2-AG), an endogenous CB1R ligand. Since: i) OX-1R and CB1R co-espression has been described at postsynaptc sites in hypothalamic circuits involved the regulation of energy homeostasis, and ii) increased orexin-A (OX-A) and 2-AG levels occur in hypothalamic neurons during obesity, we sought here to investigate the OX-1R/CB1R interaction in embryonic mouse hypothalamic NPY/AgRP mHypoE-N41 neurons which express, constitutively, both receptors...
September 2016: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
Mar Rodríguez-Ruiz, Estefanía Moreno, David Moreno-Delgado, Gemma Navarro, Josefa Mallol, Antonio Cortés, Carme Lluís, Enric I Canela, Vicent Casadó, Peter J McCormick, Rafael Franco
Alzheimer's disease (AD) is a neurodegenerative disorder causing progressive memory loss and cognitive dysfunction. Anti-AD strategies targeting cell receptors consider them as isolated units. However, many cell surface receptors cooperate and physically contact each other forming complexes having different biochemical properties than individual receptors. We here report the discovery of dopamine D1, histamine H3, and N-methyl-D-aspartate (NMDA) glutamate receptor heteromers in heterologous systems and in rodent brain cortex...
July 1, 2016: Molecular Neurobiology
Marie-Christin Lutterbey, Antje von Schaewen
We recently described that all three 6-phosphogluconate dehydrogenase (6PGDH) isoforms of Arabidopsis (PGD) with similar length show dual localization: PGD1 and PGD3 in the cytosol and in plastids, and PGD2 in the cytosol and in peroxisomes. We set out to investigate heterodimer formation, however due to only weak homodimerization of all Arabidopsis PGD isoforms in yeast cells, we conducted further protein-protein interaction studies in planta to investigate homomer versus heteromer formation and their sub-cellular localization...
July 1, 2016: Plant Signaling & Behavior
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