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https://www.readbyqxmd.com/read/28705698/receptor-activity-modifying-protein-dependent-and-independent-activation-mechanisms-in-the-coupling-of-calcitonin-gene-related-peptide-and-adrenomedullin-receptors-to-gs
#1
Michael J Woolley, Christopher A Reynolds, John Simms, Christopher S Walker, Juan Carlos Mobarec, Michael L Garelja, Alex C Conner, David R Poyner, Debbie L Hay
Calcitonin gene-related peptide (CGRP) or adrenomedullin (AM) receptors are heteromers of the calcitonin receptor-like receptor (CLR), a class B G protein-coupled receptor, and one of three receptor activity-modifying proteins (RAMPs). How CGRP and AM activate CLR and how this process is modulated by RAMPs is unclear. We have defined how CGRP and AM induce Gs-coupling in CLR-RAMP heteromers by measuring the effect of targeted mutagenesis in the CLR transmembrane domain on cAMP production, modeling the active state conformations of CGRP and AM receptors in complex with the Gs C-terminus and conducting molecular dynamics simulations in an explicitly hydrated lipidic bilayer...
July 10, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/28701349/actin-cytoskeleton-dependent-regulation-of-corticotropin-releasing-factor-receptor-heteromers
#2
Burcu Hasdemir, Shilpi Mahajan, Juan Oses-Prieto, Shreya Chand, Michael Woolley, Alma Burlingame, Dimitris K Grammatopoulos, Aditi Bhargava
Stress responses are highly nuanced and variable, but how this diversity is achieved by modulating receptor function, is largely unknown. Corticotropin-releasing factor receptors (CRFRs), class B GPCRs, are pivotal in mediating stress responses. Here we show that the two known CRFRs interact to form heteromeric complexes in HEK293 cells co-expressing both CRFRs and in vivo in mouse pancreas. Co-immunoprecipitation and mass spectrometry confirmed the presence of both CRF1R and CRF2βR, along with actin in these heteromeric complexes...
July 12, 2017: Molecular Biology of the Cell
https://www.readbyqxmd.com/read/28630296/subunit-specific-role-for-the-amino-terminal-domain-of-ampa-receptors-in-synaptic-targeting
#3
Javier Díaz-Alonso, Yujiao J Sun, Adam J Granger, Jonathan M Levy, Sabine M Blankenship, Roger A Nicoll
The amino-terminal domain (ATD) of AMPA receptors (AMPARs) accounts for approximately 50% of the protein, yet its functional role, if any, remains a mystery. We have discovered that the translocation of surface GluA1, but not GluA2, AMPAR subunits to the synapse requires the ATD. GluA1A2 heteromers in which the ATD of GluA1 is absent fail to translocate, establishing a critical role of the ATD of GluA1. Inserting GFP into the ATD interferes with the constitutive synaptic trafficking of GluA1, but not GluA2, mimicking the deletion of the ATD...
July 3, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28622290/structural-basis-for-the-regulatory-interactions-of-proapoptotic-par-4
#4
Udaya K Tiruttani Subhramanyam, Jan Kubicek, Ulf B Eidhoff, Joerg Labahn
Par-4 is a unique proapoptotic protein with the ability to induce apoptosis selectively in cancer cells. The X-ray crystal structure of the C-terminal domain of Par-4 (Par-4CC), which regulates its apoptotic function, was obtained by MAD phasing. Par-4 homodimerizes by forming a parallel coiled-coil structure. The N-terminal half of Par-4CC contains the homodimerization subdomain. This structure includes a nuclear export signal (Par-4NES) sequence, which is masked upon dimerization indicating a potential mechanism for nuclear localization...
June 16, 2017: Cell Death and Differentiation
https://www.readbyqxmd.com/read/28620024/signalling-assemblies-the-odds-of-symmetry
#5
REVIEW
Gábor Maksay, Joseph A Marsh
The assembly of proteins into complexes is fundamental to nearly all biological signalling processes. Symmetry is a dominant feature of the structures of experimentally determined protein complexes, observed in the vast majority of homomers and many heteromers. However, some asymmetric structures exist, and asymmetry also often forms transiently, intractable to traditional structure determination methods. Here, we explore the role of protein complex symmetry and asymmetry in cellular signalling, focusing on receptors, transcription factors and transmembrane channels, among other signalling assemblies...
June 15, 2017: Biochemical Society Transactions
https://www.readbyqxmd.com/read/28608532/%C3%AE-opioid-receptor-dopamine-d1-receptor-heteromers-modulate-opioid-induced-locomotor-sensitization-in-a-dopamine-independent-manner
#6
Yi-Min Tao, Chuan Yu, Wei-Sheng Wang, Yuan-Yuan Hou, Xue-Jun Xu, Zhi-Qiang Chi, Yu-Qiang Ding, Yu-Jun Wang, Jing-Gen Liu
BACKGROUND AND PURPOSE: Exposure to opiates induces locomotor sensitization in rodents, which has been proposed to correspond to the compulsive drug-seeking behavior. Numerous studies have demonstrated that locomotor sensitization can occur in a dopamine transmission-independent manner, however, the underlying mechanisms are unclear. EXPERIMENTAL APPROACH: The coimmunoprecipitation, BRET and cross-antagonism assays were used to demonstrating the existence of receptor heterodimers...
June 13, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28580231/hormones-and-neuropeptide-receptor-heteromers-in-the-ventral-tegmental-area-targets-for-the-treatment-of-loss-of-control-of-food-intake-and-substance-use-disorders
#7
REVIEW
Sergi Ferré
Hormones and neuropeptides represent biological correlates of internal homeostatic signals detected and integrated in the hypothalamus, which establishes a robust functional connection with the ventral tegmental area (VTA). The hypothalamus-VTA connection determines the ability of these signals to influence central dopaminergic neurotransmission and, therefore, their ability to increase responsiveness to their reward-associated stimuli and to establish appropriate associative learning. The hypothalamus also provides the main source of the multiple neuropeptides that are released in the VTA...
2017: Current Treatment Options in Psychiatry
https://www.readbyqxmd.com/read/28561759/heteromer-nanostars-by-spontaneous-self-assembly
#8
Caitlin Brocker, Hannah Kim, Daniel Smith, Sutapa Barua
Heteromer star-shaped nanoparticles have the potential to carry out therapeutic agents, improve intracellular uptake, and safely release drugs after prolonged periods of residence at the diseased site. A one-step seed mediation process was employed using polylactide-co-glycolic acid (PLGA), polyvinyl alcohol (PVA), silver nitrate, and tetrakis(hydroxymethyl)phosphonium chloride (THPC). Mixing these reagents followed by UV irradiation successfully produced heteromer nanostars containing a number of arm chains attached to a single core with a high yield...
May 31, 2017: Nanomaterials
https://www.readbyqxmd.com/read/28503149/vascular-kinin-b1-and-b2-receptors-determine-endothelial-dysfunction-through-neuronal-nitric-oxide-synthase
#9
Thássio R R Mesquita, Gianne P Campos-Mota, Virgínia S Lemos, Jader S Cruz, Itamar C G de Jesus, Enilton A Camargo, Jorge L Pesquero, João B Pesquero, Luciano Dos Santos A Capettini, Sandra Lauton-Santos
B1- and B2-kinin receptors are G protein-coupled receptors that play an important role in the vascular function. Therefore, the present study was designed to evaluate the participation of kinin receptors in the acetylcholine (ACh)-induced vascular relaxation, focusing on the protein-protein interaction involving kinin receptors with endothelial and neuronal nitric oxide synthases (eNOS and nNOS). Vascular reactivity, nitric oxide (NO·) and reactive oxygen species (ROS) generation, co-immunoprecipitation were assessed in thoracic aorta from male wild-type (WT), B1- (B1R(-/-)), B2- (B2R(-/-)) knockout mice...
2017: Frontiers in Physiology
https://www.readbyqxmd.com/read/28500295/angiotensin-ii-type-1-adenosine-a-2a-receptor-oligomers-a-novel-target-for-tardive-dyskinesia
#10
Paulo A de Oliveira, James A R Dalton, Marc López-Cano, Adrià Ricarte, Xavier Morató, Filipe C Matheus, Andréia S Cunha, Christa E Müller, Reinaldo N Takahashi, Víctor Fernández-Dueñas, Jesús Giraldo, Rui D Prediger, Francisco Ciruela
Tardive dyskinesia (TD) is a serious motor side effect that may appear after long-term treatment with neuroleptics and mostly mediated by dopamine D2 receptors (D2Rs). Striatal D2R functioning may be finely regulated by either adenosine A2A receptor (A2AR) or angiotensin receptor type 1 (AT1R) through putative receptor heteromers. Here, we examined whether A2AR and AT1R may oligomerize in the striatum to synergistically modulate dopaminergic transmission. First, by using bioluminescence resonance energy transfer, we demonstrated a physical AT1R-A2AR interaction in cultured cells...
May 12, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28431970/effects-of-natural-and-synthetic-isothiocyanate-based-h2s-releasers-against-chemotherapy-induced-neuropathic-pain-role-of-kv7-potassium-channels
#11
Lorenzo Di Cesare Mannelli, Elena Lucarini, Laura Micheli, Ilaria Mosca, Paolo Ambrosino, Maria Virginia Soldovieri, Alma Martelli, Lara Testai, Maurizio Taglialatela, Vincenzo Calderone, Carla Ghelardini
Hydrogen sulfide (H2S) is a crucial signaling molecule involved in several physiological and pathological processes. Nonetheless, the role of this gasotransmitter in the pathogenesis and treatment of neuropathic pain is controversial. The aim of the present study was to investigate the pain relieving profile of a series of slow releasing H2S donors (the natural allyl-isothiocyanate and the synthetics phenyl- and carboxyphenyl-isothiocyanate) in animal models of neuropathic pain induced by paclitaxel or oxaliplatin, anticancer drugs characterized by a dose-limiting neurotoxicity...
April 19, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28415220/multistage-modeling-of-protein-dynamics-with-monomeric-myc-oncoprotein-as-an-example
#12
Jiaojiao Liu, Jin Dai, Jianfeng He, Antti J Niemi, Nevena Ilieva
We propose to combine a mean-field approach with all-atom molecular dynamics (MD) into a multistage algorithm that can model protein folding and dynamics over very long time periods yet with atomic-level precision. As an example, we investigate an isolated monomeric Myc oncoprotein that has been implicated in carcinomas including those in colon, breast, and lungs. Under physiological conditions a monomeric Myc is presumed to be an example of intrinsically disordered proteins that pose a serious challenge to existing modeling techniques...
March 2017: Physical Review. E
https://www.readbyqxmd.com/read/28397834/snon-stabilizes-the-smad3-smad4-protein-complex
#13
Karin Walldén, Tomas Nyman, B Martin Hällberg
TGF-β signaling regulates cellular processes such as proliferation, differentiation and apoptosis through activation of SMAD transcription factors that are in turn modulated by members of the Ski-SnoN family. In this process, Ski has been shown to negatively modulate TGF-β signaling by disrupting active R-SMAD/Co-SMAD heteromers. Here, we show that the related regulator SnoN forms a stable complex with the R-SMAD (SMAD3) and the Co-SMAD (SMAD4). To rationalize this stabilization at the molecular level, we determined the crystal structure of a complex between the SAND domain of SnoN and the MH2-domain of SMAD4...
April 11, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28265090/deactivation-kinetics-of-acid-sensing-ion-channel-1a-are-strongly-ph-sensitive
#14
David M MacLean, Vasanthi Jayaraman
Acid-sensing ion channels (ASICs) are trimeric cation-selective ion channels activated by protons in the physiological range. Recent reports have revealed that postsynaptically localized ASICs contribute to the excitatory postsynaptic current by responding to the transient acidification of the synaptic cleft that accompanies neurotransmission. In response to such brief acidic transients, both recombinant and native ASICs show extremely rapid deactivation in outside-out patches when jumping from a pH 5 stimulus to a single resting pH of 8...
March 21, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28261115/il1r2-ccr2-and-cxcr4-may-form-heteroreceptor-complexes-with-nmdar-and-d2r-relevance-for-schizophrenia
#15
Dasiel O Borroto-Escuela, Alexander O Tarakanov, Karl Bechter, Kjell Fuxe
The mild neuroinflammation hypothesis of schizophrenia was introduced by Bechter in 2001. It has been hypothesized that a hypofunction of glutamatergic signaling via N-methyl-D-aspartate receptors (NMDARs) and hyperactivation of dopamine D2 receptors play a role in schizophrenia. The triplet puzzle theory states that sets of triplet amino acid homologies guide two different receptors toward each other and contributes to the formation of a receptor heteromer. It is, therefore, proposed that putative NMDAR-C-C chemokine receptor type 2 (CCR2), NMDAR-C-X-C chemokine receptor type 4 (CXCR4), and NMDAR- interleukin 1 receptor type II (IL1R2) heteromers can be formed in the neuronal networks in mild neuroinflammation due to demonstration of Gly-Leu-Leu (GLL), Val-Ser-Thr (VST), and/or Ser-Val-Ser (SVS) amino acid homologies between these receptor protomers...
2017: Frontiers in Psychiatry
https://www.readbyqxmd.com/read/28218424/p16-ink4a-enhances-the-transcriptional-and-the-apoptotic-functions-of-p53-through-dna-dependent-interaction
#16
Huda H Al-Khalaf, Shreeram C Nallar, Dhananjaya V Kalvakolanu, Abdelilah Aboussekhra
p16(INK4A) and p53 are two important tumor suppressor proteins that play essential roles during cell proliferation and aging through regulating the expression of several genes. Here, we report that p16(INK4A) and p53 co-regulate a plethora of transcripts. Furthermore, both proteins colocalize in the nucleus of human primary skin fibroblasts and breast luminal cells, and form a heteromer whose level increases in response to genotoxic stress as well as aging of human fibroblasts and various mouse organs. CDK4 is also present in this heteromeric complex, which is formed only in the presence of DNA both in vitro using pure recombinant proteins and in vivo...
February 20, 2017: Molecular Carcinogenesis
https://www.readbyqxmd.com/read/28215100/targeting-baff-and-april-in-systemic-lupus-erythematosus-and-other-antibody-associated-diseases
#17
Eileen Samy, Stephen Wax, Bertrand Huard, Henry Hess, Pascal Schneider
The B cell-stimulating molecules, BAFF (B cell activating factor) and APRIL (a proliferation-inducing ligand), are critical factors in the maintenance of the B cell pool and humoral immunity. In addition, BAFF and APRIL are involved in the pathogenesis of a number of human autoimmune diseases, with elevated levels of these cytokines detected in the sera of patients with systemic lupus erythematosus (SLE), IgA nephropathy, Sjögren's syndrome, and rheumatoid arthritis. As such, both molecules are rational targets for new therapies in B cell-driven autoimmune diseases, and several inhibitors of BAFF or BAFF and APRIL together have been investigated in clinical trials...
January 2, 2017: International Reviews of Immunology
https://www.readbyqxmd.com/read/28193731/selective-transport-of-neurotransmitters-and-modulators-by-distinct-volume-regulated-lrrc8-anion-channels
#18
Darius Lutter, Florian Ullrich, Jennifer C Lueck, Stefan Kempa, Thomas J Jentsch
In response to swelling, mammalian cells release chloride and organic osmolytes through VRAC volume-regulated anion channels. VRACs are heteromers of LRRC8A and other LRRC8 isoforms (B-E) which are co-expressed in HEK293 and most other cells. The spectrum of VRAC substrates and its dependence on particular LRRC8 isoforms remains largely unknown. We show that besides the osmolytes taurine and myo-inositol, LRRC8 channels transport the neurotransmitters glutamate, aspartate and GABA and the co-activator D-serine...
February 13, 2017: Journal of Cell Science
https://www.readbyqxmd.com/read/28187919/dopamine-d3-and-acetylcholine-nicotinic-receptor-heteromerization-in-midbrain-dopamine-neurons-relevance-for-neuroplasticity
#19
Leonardo Bontempi, Paola Savoia, Federica Bono, Chiara Fiorentini, Cristina Missale
Activation of nicotinic acetylcholine receptors (nAChR) promotes the morphological remodeling of cultured dopamine (DA) neurons, an effect requiring functional DA D3 receptors (D3R). The aim of this study was to investigate the mechanisms mediating D3R-nAChR cross-talk in the modulation of DA neuron structural plasticity. By using bioluminescence resonance energy transfer(2) (BRET(2)) and proximity ligation assay (PLA), evidence for the existence of D3R-nAChR heteromers has been obtained. In particular, BRET(2) showed that the D3R directly and specifically interacts with the β2 subunit of the nAChR...
February 7, 2017: European Neuropsychopharmacology: the Journal of the European College of Neuropsychopharmacology
https://www.readbyqxmd.com/read/28187393/shape-controlled-fabrication-of-magnetite-silver-hybrid-nanoparticles-with-high-performance-magnetic-hyperthermia
#20
Qi Ding, Dongfang Liu, Dawei Guo, Fang Yang, Xingyun Pang, Renchao Che, Naizhen Zhou, Jun Xie, Jianfei Sun, Zhihai Huang, Ning Gu
Superparamagnetic Fe3O4 nanoparticles (NPs)-based hyperthermia is a promising non-invasive approach for cancer therapy. However, the heat transfer efficiency of Fe3O4 NPs is relative low, which hinders their practical clinical applications. Therefore, it is promising to improve the magnetic hyperthermia efficiency by exploring the higher performance magnetic NPs-based hybrid nanostructures. In the current study, it presents a straightforward in situ reduction method for the shape-controlled preparation of magnetite (Fe3O4) silver (Ag) hybrid NPs designed as magnetic hyperthermia heat mediators...
January 31, 2017: Biomaterials
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