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https://www.readbyqxmd.com/read/29317777/a-kinase-anchoring-protein-150-akap150-promotes-cocaine-reinstatement-by-increasing-ampa-receptor-transmission-in-the-accumbens-shell
#1
Leonardo A Guercio, Mackenzie E Hofmann, Sarah E Swinford-Jackson, Julia S Sigman, Mathieu E Wimmer, Mark L Dell'Acqua, Heath D Schmidt, R Christopher Pierce
Previous work indicated that activation of D1-like dopamine receptors (D1DRs) in the nucleus accumbens shell promoted cocaine seeking through a process involving the activation of PKA and GluA1-containing AMPA receptors (AMPARs). A-kinase anchoring proteins (AKAPs) localize PKA to AMPARs leading to enhanced phosphorylation of GluA1. AKAP150, the most well-characterized isoform, plays an important role in several forms of neuronal plasticity. However, its involvement in drug addiction has been minimally explored...
December 12, 2017: Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology
https://www.readbyqxmd.com/read/29288530/pka-binding-domain-of-akap8-is-essential-for-direct-interaction-with-dpy30-protein
#2
Anna Bieluszewska, Martyna Weglewska, Tomasz Bieluszewski, Krzysztof Lesniewicz, Elzbieta Poreba
The main function of the A kinase-anchoring proteins (AKAPs) is to target the cAMP-dependent protein kinase A (PKA) to its cellular substrates through the interaction with its regulatory subunits. Besides anchoring of PKA, AKAP8 participates in regulating the H3K4 histone methyltransferase (HMT) complexes. It is also involved in DNA replication, apoptosis, transcriptional silencing of rRNA genes, alternative splicing, and chromatin condensation during mitosis. In this study, we focused on the interaction between AKAP8 and the core subunit of all known H3K4 HMT complexes-DPY30 protein...
December 30, 2017: FEBS Journal
https://www.readbyqxmd.com/read/29262295/potential-for-therapeutic-targeting-of-akap-signaling-complexes-in-nervous-system-disorders
#3
REVIEW
Angela R Wild, Mark L Dell'Acqua
A common feature of neurological and neuropsychiatric disorders is a breakdown in the integrity of intracellular signal transduction pathways. Dysregulation of ion channels and receptors in the cell membrane and the enzymatic mediators that link them to intracellular effectors can lead to synaptic dysfunction and neuronal death. However, therapeutic targeting of these ubiquitous signaling elements can lead to off-target side effects due to their widespread expression in multiple systems of the body. A-kinase anchoring proteins (AKAPs) are multivalent scaffolding proteins that compartmentalize a diverse range of receptor and effector proteins to streamline signaling within nanodomain signalosomes...
December 17, 2017: Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/29247678/absence-of-synemin-in-mice-causes-structural-and-functional-abnormalities-in-heart
#4
Karla P García-Pelagio, Ling Chen, Humberto C Joca, Christopher Ward, W Jonathan Lederer, Robert J Bloch
Cardiomyopathies have been linked to changes in structural proteins, including intermediate filament (IF) proteins located in the cytoskeleton. IFs associate with the contractile machinery and costameres of striated muscle and with intercalated disks in the heart. Synemin is a large IF protein that mediates the association of desmin with Z-disks and stabilizes intercalated disks. It also acts as an A-kinase anchoring protein (AKAP). In murine skeletal muscle, the absence of synemin causes a mild myopathy. Here, we report that the genetic silencing of synemin in mice (synm -/-) causes left ventricular systolic dysfunction at 3months and 12-16months of age, and left ventricular hypertrophy and dilatation at 12-16months of age...
December 13, 2017: Journal of Molecular and Cellular Cardiology
https://www.readbyqxmd.com/read/29196604/camkii-regulates-the-de-palmitoylation-and-synaptic-removal-of-akap79-150-to-mediate-structural-ltd
#5
Kevin M Woolfrey, Heather O'Leary, Dayton J Goodell, Holly R Robertson, Eric A Horne, Steven J Coultrap, Mark L Dell'Acqua, K Ulrich Bayer
Both long-term potentiation (LTP) and depression (LTD) of excitatory synapse strength require the Ca2+/calmodulin (CaM)-dependent protein kinase II (CaMKII) and its autonomous activity generated by T286 autophosphorylation. Additionally, LTP and LTD are correlated with dendritic spine enlargement and shrinkage that are accompanied by the synaptic accumulation or removal, respectively, of the AMPA-receptor regulatory scaffold protein A-kinase anchoring protein (AKAP) 79/150. We show here that the spine shrinkage associated with LTD indeed requires synaptic AKAP79/150 removal, which in turn requires CaMKII activity...
December 1, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29123182/identification-of-a-novel-camp-dependent-protein-kinase-a-phosphorylation-site-on-the-human-cardiac-calcium-channel
#6
Henrietta Cserne Szappanos, Padmapriya Muralidharan, Evan Ingley, Jakob Petereit, Harvey A Millar, Livia C Hool
The "Fight or Flight" response is elicited by extrinsic stress and is necessary in many species for survival. The response involves activation of the β-adrenergic signalling pathway. Surprisingly the mechanisms have remained unresolved. Calcium influx through the cardiac L-type Ca(2+) channel (Cav1.2) is absolutely required. Here we identify the functionally relevant site for PKA phosphorylation on the human cardiac L-type Ca(2+) channel pore forming α1 subunit using a novel approach. We used a cell free system where we could assess direct effects of PKA on human purified channel protein function reconstituted in proteoliposomes...
November 9, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28927666/the-role-of-a-kinase-anchoring-proteins-in-cancer-development
#7
REVIEW
Erica Reggi, Dario Diviani
Cancer development is a multifactorial process resulting from the aberrant activation of multiple signaling pathways. It has become increasingly clear that the coordination of the signaling events leading to cancer formation and progression is under the control of macromolecular transduction complexes organized by scaffolding proteins. A-kinase anchoring proteins (AKAPs) constitute a family of scaffolding proteins involved in the spatio-temporal activation of pathways controlling cancer cell proliferation, cell survival, and invasion...
December 2017: Cellular Signalling
https://www.readbyqxmd.com/read/28923249/akap-lbc-mediates-protection-against-doxorubicin-induced-cardiomyocyte-toxicity
#8
Stefania Caso, Darko Maric, Miroslav Arambasic, Susanna Cotecchia, Dario Diviani
Doxorubicin (DOX) is a chemotherapic agent that is widely used to treat hematological and solid tumors. Despite its efficacy, DOX displays significant cardiac toxicity associated with cardiomyocytes death and heart failure. Cardiac toxicity is mainly associated with the ability of DOX to alter mitochondrial function. The current lack of treatments to efficiently prevent DOX cardiotoxicity underscores the need of new therapeutic approaches. Our current findings show that stimulation of cardiomyocytes with the α1-adrenergic receptor (AR) agonist phenylephrine (PE) significantly inhibits the apoptotic effect of DOX...
December 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28676344/crispr-epigenome-editing-of-akap150-in-drg-neurons-abolishes-degenerative-ivd-induced-neuronal-activation
#9
Joshua D Stover, Niloofar Farhang, Kristofer C Berrett, Jason Gertz, Brandon Lawrence, Robby D Bowles
Back pain is a major contributor to disability and has significant socioeconomic impacts worldwide. The degenerative intervertebral disc (IVD) has been hypothesized to contribute to back pain, but a better understanding of the interactions between the degenerative IVD and nociceptive neurons innervating the disc and treatment strategies that directly target these interactions is needed to improve our understanding and treatment of back pain. We investigated degenerative IVD-induced changes to dorsal root ganglion (DRG) neuron activity and utilized CRISPR epigenome editing as a neuromodulation strategy...
September 6, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28642438/local-protein-kinase-a-action-proceeds-through-intact-holoenzymes
#10
F Donelson Smith, Jessica L Esseltine, Patrick J Nygren, David Veesler, Dominic P Byrne, Matthias Vonderach, Ilya Strashnov, Claire E Eyers, Patrick A Eyers, Lorene K Langeberg, John D Scott
Hormones can transmit signals through adenosine 3',5'-monophosphate (cAMP) to precise intracellular locations. The fidelity of these responses relies on the activation of localized protein kinase A (PKA) holoenzymes. Association of PKA regulatory type II (RII) subunits with A-kinase-anchoring proteins (AKAPs) confers location, and catalytic (C) subunits phosphorylate substrates. Single-particle electron microscopy demonstrated that AKAP79 constrains RII-C subassemblies within 150 to 250 angstroms of its targets...
June 23, 2017: Science
https://www.readbyqxmd.com/read/28528970/the-many-faces-of-compartmentalized-pka-signalosomes
#11
REVIEW
Omar Torres-Quesada, Johanna E Mayrhofer, Eduard Stefan
Cellular signal transmission requires the dynamic formation of spatiotemporally controlled molecular interactions. At the cell surface information is received by receptor complexes and relayed through intracellular signaling platforms which organize the actions of functionally interacting signaling enzymes and substrates. The list of hormone or neurotransmitter pathways that utilize the ubiquitous cAMP-sensing protein kinase A (PKA) system is expansive. This requires that the specificity, duration, and intensity of PKA responses are spatially and temporally restricted...
May 18, 2017: Cellular Signalling
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
#12
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-motif-dependent-and-independent-mechanisms
#13
COMPARATIVE STUDY
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 Here, we show that GPR30 also constitutively increases ERK1/2 activity...
June 16, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28427098/opa1-in-lipid-metabolism-function-of-opa1-in-lipolysis-and-thermogenesis-of-adipocytes
#14
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
#15
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
#16
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-%C3%AE-opioid-receptor-incompetence-in-peripheral-sensory-neurons
#17
Allison Doyle Brackley, Shayda Sarrami, Ruben Gomez, Kristi A Guerrero, Nathaniel A Jeske
μ-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 δ-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...
May 26, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28372987/disrupting-sensitization-of-trpv4
#18
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
#19
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...
May 2017: Naunyn-Schmiedeberg's Archives of Pharmacology
https://www.readbyqxmd.com/read/28192412/akap-mediated-feedback-control-of-camp-gradients-in-developing-hippocampal-neurons
#20
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
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