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https://www.readbyqxmd.com/read/28500286/a-kinase-anchoring-protein-79-150-scaffolds-transient-receptor-potential-a-1-phosphorylation-and-sensitization-by-metabotropic-glutamate-receptor-activation
#1
Allison Doyle Brackley, Ruben Gomez, Kristi A Guerrero, Armen N Akopian, Marc J Glucksman, Junhui Du, Susan M Carlton, Nathaniel A Jeske
Mechanical pain serves as a base clinical symptom for many of the world's most debilitating syndromes. Ion channels expressed by peripheral sensory neurons largely contribute to mechanical hypersensitivity. Transient Receptor Potential A 1 (TRPA1) is a ligand-gated ion channel that contributes to inflammatory mechanical hypersensitivity, yet little is known as to the post-translational mechanism behind its somatosensitization. Here, we utilize biochemical, electrophysiological, and behavioral measures to demonstrate that metabotropic glutamate receptor-induced sensitization of TRPA1 nociceptors stimulates targeted modification of the receptor...
May 12, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28450397/g-protein-coupled-estrogen-receptor-1-gper1-gpr30-increases-erk1-2-activity-through-pdz-dependent-and-independent-mechanisms
#2
Ernesto Gonzalez de Valdivia, Stefan Broselid, Robin Kahn, Björn Olde, L M Fredrik Leeb-Lundberg
G protein-coupled receptor 30 (GPR30), also called G protein-coupled estrogen receptor 1 (GPER1), is thought to play important roles in breast cancer and cardiometabolic regulation, but many questions remain about ligand activation, effector coupling, and subcellular localization. We showed recently that GPR30 interacts through the C-terminal type I PDZ motif with SAP97 and protein kinase A (PKA)-anchoring protein (AKAP) 5, which anchor the receptor in the plasma membrane and mediate an apparently constitutive decrease in cAMP production independently of Gi/o...
April 27, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28427098/opa1-in-lipid-metabolism-function-of-opa1-in-lipolysis-and-thermogenesis-of-adipocytes
#3
Dinh-Toi Chu, Yang Tao, Kjetil Taskén
OPA1 (Optic Atrophy 1) is a mitochondrial GTPase known to regulate fission of mitochondria. It was recently also shown to locate on lipid droplets in adipocytes where it functions as an A-kinase anchoring protein (AKAP) that mediates adrenergic control of lipolysis by facilitating PKA phosphorylation of perilipin (Plin1). In brown adipocytes indirect evidence support the notion that OPA1 regulation of fission serves to increase thermogenesis, which thereby contributes to dissipation of energy. In white adipocytes, OPA1 located on lipid droplets serves as a gatekeeper to control lipolysis induced by adrenergic agonists...
April 2017: Hormone and Metabolic Research, Hormon- und Stoffwechselforschung, Hormones et Métabolisme
https://www.readbyqxmd.com/read/28423323/liberated-pka-catalytic-subunits-associate-with-the-membrane-via-myristoylation-to-preferentially-phosphorylate-membrane-substrates
#4
Shane E Tillo, Wei-Hong Xiong, Maho Takahashi, Sheng Miao, Adriana L Andrade, Dale A Fortin, Guang Yang, Maozhen Qin, Barbara F Smoody, Philip J S Stork, Haining Zhong
Protein kinase A (PKA) has diverse functions in neurons. At rest, the subcellular localization of PKA is controlled by A-kinase anchoring proteins (AKAPs). However, the dynamics of PKA upon activation remain poorly understood. Here, we report that elevation of cyclic AMP (cAMP) in neuronal dendrites causes a significant percentage of the PKA catalytic subunit (PKA-C) molecules to be released from the regulatory subunit (PKA-R). Liberated PKA-C becomes associated with the membrane via N-terminal myristoylation...
April 18, 2017: Cell Reports
https://www.readbyqxmd.com/read/28408477/pseudoscaffolds-and-anchoring-proteins-the-difference-is-in-the-details
#5
REVIEW
Stacey Aggarwal-Howarth, John D Scott
Pseudokinases and pseudophosphatases possess the ability to bind substrates without catalyzing their modification, thereby providing a mechanism to recruit potential phosphotargets away from active enzymes. Since many of these pseudoenzymes possess other characteristics such as localization signals, separate catalytic sites, and protein-protein interaction domains, they have the capacity to influence signaling dynamics in local environments. In a similar manner, the targeting of signaling enzymes to subcellular locations by A-kinase-anchoring proteins (AKAPs) allows for precise and local control of second messenger signaling events...
April 15, 2017: Biochemical Society Transactions
https://www.readbyqxmd.com/read/28381559/identification-of-a-signaling-cascade-that-maintains-constitutive-delta-opioid-receptor-incompetence-in-peripheral-sensory-neurons
#6
Allison Doyle Brackley, Shayda Sarrami, Ruben Gomez, Kristi A Guerrero, Nathaniel A Jeske
Mu opioid receptor (MOR) agonists are often used to treat severe pain, but can result in adverse side effects. To circumvent systemic side effects, targeting peripheral opioid receptors is an attractive alternative treatment for severe pain. Activation of the delta opioid receptor (DOR) produces similar analgesia with reduced side effects. However, until primed by inflammation, peripheral DOR is analgesically incompetent, raising interest in the mechanism. We recently identified a novel role for G protein-coupled receptor kinase 2 (GRK2) that renders DOR analgesically incompetent at the plasma membrane...
April 5, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28372987/disrupting-sensitization-of-trpv4
#7
Konrad Mack, Michael J M Fischer
TRPV4 ion channels have a broad expression profile and were shown to contribute to enhanced pain sensation in inflammation. Directly blocking TRPV4 might run the risk of interfering with normal physiology, and has prompted to explore the interaction with the scaffolding protein AKAP79, an approach successfully used for TRPV1 channels. HEK293t cells express AKAP79, additional transfection did not sensitize human TRPV4. Application of trypsin facilitated responses to TRPV4 agonist GSK1016790A. Using a specific protease-activated receptor 2 agonist, involvement of an A-kinase anchoring protein in TRPV4 activation was demonstrated by inhibition with AKAP inhibitor peptide Ht31...
June 3, 2017: Neuroscience
https://www.readbyqxmd.com/read/28331977/role-of-plasma-membrane-associated-akaps-for-the-regulation-of-cardiac-ik1-current-by-protein-kinase-a
#8
Claudia Seyler, Daniel Scherer, Christoph Köpple, Martin Kulzer, Sevil Korkmaz, Panagiotis Xynogalos, Dierk Thomas, Ziya Kaya, Eberhard Scholz, Johannes Backs, Christoph Karle, Hugo A Katus, Edgar Zitron
The cardiac IK1 current stabilizes the resting membrane potential of cardiomyocytes. Protein kinase A (PKA) induces an inhibition of IK1 current which strongly promotes focal arrhythmogenesis. The molecular mechanisms underlying this regulation have only partially been elucidated yet. Furthermore, the role of A-kinase anchoring proteins (AKAPs) in this regulation has not been examined to date. The objective of this project was to elucidate the molecular mechanisms underlying the inhibition of IK1 by PKA and to identify novel molecular targets for antiarrhythmic therapy downstream β-adrenoreceptors...
March 22, 2017: Naunyn-Schmiedeberg's Archives of Pharmacology
https://www.readbyqxmd.com/read/28192412/akap-mediated-feedback-control-of-camp-gradients-in-developing-hippocampal-neurons
#9
Kirill Gorshkov, Sohum Mehta, Santosh Ramamurthy, Gabriele V Ronnett, Feng-Quan Zhou, Jin Zhang
Cyclic AMP (cAMP) and protein kinase A (PKA), classical examples of spatially compartmentalized signaling molecules, are critical axon determinants that regulate neuronal polarity and axon formation, yet little is known about micro-compartmentalization of cAMP and PKA signaling and its role in developing neurons. Here, we revealed that cAMP forms a gradient in developing hippocampal neurons, with higher cAMP levels in more distal regions of the axon compared to other regions of the cell. Interestingly, this cAMP gradient changed according to the developmental stage and depended on proper anchoring of PKA by A-kinase anchoring proteins (AKAPs)...
April 2017: Nature Chemical Biology
https://www.readbyqxmd.com/read/28164467/microtubule-regulating-proteins-and-camp-dependent-signaling-in-neuroblastoma-differentiation
#10
Pablo Muñoz-Llancao, Cristian de Gregorio, Macarena Las Heras, Christopher Meinohl, Kevin Noorman, Erik Boddeke, Xiaodong Cheng, Frank Lezoualc'h, Martina Schmidt, Christian Gonzalez-Billault
Neurons are highly differentiated cells responsible for the conduction and transmission of information in the nervous system. The proper function of a neuron relies on the compartmentalization of their intracellular domains. Differentiated neuroblastoma cells have been extensively used to study and understand the physiology and cell biology of neuronal cells. Here, we show that differentiation of N1E-115 neuroblastoma cells is more pronounced upon exposure of a chemical analog of cyclic AMP (cAMP), db-cAMP...
March 2017: Cytoskeleton
https://www.readbyqxmd.com/read/28119464/ser1928-phosphorylation-by-pka-stimulates-the-l-type-ca2-channel-cav1-2-and-vasoconstriction-during-acute-hyperglycemia-and-diabetes
#11
Matthew A Nystoriak, Madeline Nieves-Cintrón, Tommaso Patriarchi, Olivia R Buonarati, Maria Paz Prada, Stefano Morotti, Eleonora Grandi, Julia Dos Santos Fernandes, Katherine Forbush, Franz Hofmann, Kent C Sasse, John D Scott, Sean M Ward, Johannes W Hell, Manuel F Navedo
Hypercontractility of arterial myocytes and enhanced vascular tone during diabetes are, in part, attributed to the effects of increased glucose (hyperglycemia) on L-type CaV1.2 channels. In murine arterial myocytes, kinase-dependent mechanisms mediate the increase in CaV1.2 activity in response to increased extracellular glucose. We identified a subpopulation of the CaV1.2 channel pore-forming subunit (α1C) within nanometer proximity of protein kinase A (PKA) at the sarcolemma of murine and human arterial myocytes...
January 24, 2017: Science Signaling
https://www.readbyqxmd.com/read/28077322/a-protein-kinase-a-ezrin-complex-regulates-connexin-43-gap-junction-communication-in-liver-epithelial-cells
#12
Aleksandra R Dukic, Linda Hofstad Haugen, Guillaume Pidoux, Edward Leithe, Oddmund Bakke, Kjetil Taskén
Communication between adjacent cells can occur via gap junctions (GJ) composed of connexin (Cx) hexamers that allow passage of small molecules. One of the most widely and highly expressed Cxs in human tissues is Cx43, shown to be regulated through phosphorylation by several kinases including PKA. Ezrin is a membrane associated protein that can serve as an A-kinase anchoring protein (AKAP) and hold an anchored pool of PKA. Here, we used the liver epithelial cell line IAR20, which expresses Cx43 as the predominant GJ protein, to test the hypothesis that Ezrin may associate with Cx43 in cell types that form stable GJs and serve as an AKAP...
January 8, 2017: Cellular Signalling
https://www.readbyqxmd.com/read/28076805/regulation-of-active-icam-4-on-normal-and-sickle-cell-disease-rbcs-via-akaps-is-revealed-by-afm
#13
Jing Zhang, Krithika Abiraman, Sasia-Marie Jones, George Lykotrafitis, Biree Andemariam
Human healthy (wild-type (WT)) and homozygous sickle (SS) red blood cells (RBCs) express a large number of surface receptors that mediate cell adhesion between RBCs, and between RBCs and white blood cells, platelets, and the endothelium. In sickle cell disease (SCD), abnormal adhesion of RBCs to endothelial cells is mediated by the intercellular adhesion molecule-4 (ICAM-4), which appears on the RBC membrane and binds to the endothelial αvβ3 integrin. This is a key factor in the initiation of vaso-occlusive episodes, the hallmark of SCD...
January 10, 2017: Biophysical Journal
https://www.readbyqxmd.com/read/28063348/the-in-silico-identification-of-small-molecules-for-protein-protein-interaction-inhibition-in-akap-lbc-rhoa-signaling-complex
#14
Asifullah Khan, Mehwish Munir, Sara Aiman, Abdul Wadood, Arif-Ullah Khan
The rational design of small molecules that mimic key residues at the interface of interacting proteins can be a successful approach to target certain biological signaling cascades causing pathophysiological outcome. The A-Kinase Anchoring Protein, i.e. AKAP-Lbc, catalyses nucleotide exchange on RhoA and is involved in cardiac repolarization. The oncogenic AKAP-Lbc induces the RhoA GTPase hyperactivity and aberrantly amplifies the signaling pathway leading to hypertrophic cardiomyocytes. We took advantage of the AKAP-Lbc-RhoA complex crystal structure to design in silico small molecules predicted to inhibit the associated pathological signaling cascade...
December 31, 2016: Computational Biology and Chemistry
https://www.readbyqxmd.com/read/28003270/akap-mediated-signalling-the-importance-of-being-in-the-right-place-at-the-right-time
#15
EDITORIAL
Cinzia Perrino, Bruno Trimarco
No abstract text is available yet for this article.
February 2017: Cardiovascular Research
https://www.readbyqxmd.com/read/27901058/a-kinase-anchoring-protein-4-akap4-is-an-erk1-2-substrate-and-a-switch-molecule-between-camp-pka-and-pkc-erk1-2-in-human-spermatozoa
#16
Liat Rahamim Ben-Navi, Tal Almog, Zhong Yao, Rony Seger, Zvi Naor
Mammalian spermatozoa undergo capacitation and acrosome reaction in order to fertilize the egg. The PKC-ERK1/2 pathway plays an important role in human spermatozoa motility, capacitation and the acrosome reaction. Here we demonstrate that ERK1/2 phosphorylates proAKAP4 on Thr265 in human spermatozoa in vitro and in vivo. Cyclic AMP (cAMP) had no effect on ERK1/2 activity in human spermatozoa, but stimulated the MAPK in mouse pituitary LβT2 gonadotrope cells. cAMP via PKA attenuates PKC-dependent ERK1/2 activation only in the presence of proAKAP4...
November 30, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27835919/pka-and-apicomplexan-parasite-diseases
#17
M Haidar, G Ramdani, E J Kennedy, G Langsley
The cAMP-dependent protein kinase PKA is a well-characterized member of the serine-threonine protein AGC kinase family and is the effector kinase of cAMP signaling. As such, PKA is involved in the control of a wide variety of cellular processes including metabolism, cell growth, gene expression and apoptosis. cAMP-dependent PKA signaling pathways play important roles during infection and virulence of various pathogens. Since fluxes in cAMP are involved in multiple intracellular functions, a variety of different pathological infectious processes can be affected by PKA signaling pathways...
April 2017: Hormone and Metabolic Research, Hormon- und Stoffwechselforschung, Hormones et Métabolisme
https://www.readbyqxmd.com/read/27813475/-role-and-regulation-of-camp-signaling-in-human-trophoblast-fusion
#18
REVIEW
Pascale Gerbaud, Fatima Ferreira, Guillaume Pidoux
In the human placenta, mononuclear cytotrophoblasts fuse to form multinucleated syncytia ensuring hormonal production and nutrient exchanges between the maternal and fetal circulation. The syncytial formation is necessary for the maintenance of pregnancy and for fetal growth. The cAMP signaling pathway is the major route to trigger trophoblast fusion and its activation results in phosphorylation of specific intracellular target proteins and assembly of macromolecular protein complexes constituting the fusogenic machinery at the plasma membrane...
2016: Biologie Aujourd'hui
https://www.readbyqxmd.com/read/27693258/clustering-and-functional-coupling-of-diverse-ion-channels-and-signaling-proteins-revealed-by-super-resolution-storm-microscopy-in-neurons
#19
Jie Zhang, Chase M Carver, Frank S Choveau, Mark S Shapiro
The fidelity of neuronal signaling requires organization of signaling molecules into macromolecular complexes, whose components are in intimate proximity. The intrinsic diffraction limit of light makes visualization of individual signaling complexes using visible light extremely difficult. However, using super-resolution stochastic optical reconstruction microscopy (STORM), we observed intimate association of individual molecules within signaling complexes containing ion channels (M-type K(+), L-type Ca(2+), or TRPV1 channels) and G protein-coupled receptors coupled by the scaffolding protein A-kinase-anchoring protein (AKAP)79/150...
September 27, 2016: Neuron
https://www.readbyqxmd.com/read/27628689/a-cell-based-high-throughput-assay-for-gap-junction-communication-suitable-for-assessing-connexin-43-ezrin-interaction-disruptors-using-incucyte-zoom
#20
Aleksandra R Dukic, David W McClymont, Kjetil Taskén
Connexin 43 (Cx43), the predominant gap junction (GJ) protein, directly interacts with the A-kinase-anchoring protein (AKAP) Ezrin in human cytotrophoblasts and a rat liver epithelial cells (IAR20). The Cx43-Ezrin-protein kinase (PKA) complex facilitates Cx43 phosphorylation by PKA, which triggers GJ opening in cytotrophoblasts and IAR20 cells and may be a general mechanism regulating GJ intercellular communication (GJIC). Considering the importance of Cx43 GJs in health and disease, they are considered potential pharmaceutical targets...
January 2017: SLAS Discovery
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