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Maria Ercu, Enno Klussmann
A-kinase anchoring proteins (AKAPs) and cyclic nucleotide phosphodiesterases (PDEs) are essential enzymes in the cyclic adenosine 3'-5' monophosphate (cAMP) signaling cascade. They establish local cAMP pools by controlling the intensity, duration and compartmentalization of cyclic nucleotide-dependent signaling. Various members of the AKAP and PDE families are expressed in the cardiovascular system and direct important processes maintaining homeostatic functioning of the heart and vasculature, e.g., the endothelial barrier function and excitation-contraction coupling...
February 20, 2018: Journal of Cardiovascular Development and Disease
N George Bendzunas, Sabrina Dörfler, Karolin Autenrieth, Daniela Bertinetti, Erik M F Machal, Eileen J Kennedy, Friedrich W Herberg
Generation of the second messenger molecule cAMP mediates a variety of cellular responses which are essential for critical cellular processes. In response to elevated cAMP levels, cAMP dependent protein kinase (PKA) phosphorylates serine and threonine residues on a wide variety of target substrates. In order to enhance the precision and directionality of these signaling events, PKA is localized to discrete locations within the cell by A-kinase anchoring proteins (AKAPs). The interaction between PKA and AKAPs is mediated via an amphipathic α-helix derived from AKAPs which binds to a stable hydrophobic groove formed in the dimerization/docking (D/D) domain of PKA-R in an isoform-specific fashion...
February 12, 2018: Bioorganic & Medicinal Chemistry
Una Kjällquist, Rikard Erlandsson, Nicholas P Tobin, Amjad Alkodsi, Ikram Ullah, Gustav Stålhammar, Eva Karlsson, Thomas Hatschek, Johan Hartman, Sten Linnarsson, Jonas Bergh
BACKGROUND: Tumor heterogeneity in breast cancer tumors is today widely recognized. Most of the available knowledge in genetic variation however, relates to the primary tumor while metastatic lesions are much less studied. Many studies have revealed marked alterations of standard prognostic and predictive factors during tumor progression. Characterization of paired primary- and metastatic tissues should therefore be fundamental in order to understand mechanisms of tumor progression, clonal relationship to tumor evolution as well as the therapeutic aspects of systemic disease...
February 12, 2018: BMC Cancer
Dario Diviani, Halima Osman, Erica Reggi
Heart failure is a lethal disease that can develop after myocardial infarction, hypertension, or anticancer therapy. In the damaged heart, loss of function is mainly due to cardiomyocyte death and associated cardiac remodeling and fibrosis. In this context, A-kinase anchoring proteins (AKAPs) constitute a family of scaffolding proteins that facilitate the spatiotemporal activation of the cyclic adenosine monophosphate (AMP)-dependent protein kinase (PKA) and other transduction enzymes involved in cardiac remodeling...
February 8, 2018: Journal of Cardiovascular Development and Disease
Venkata R Narala, Jutaro Fukumoto, Helena Hernández-Cuervo, Sahebgowda Sidramagowda Patil, Sudarshan Krishnamurthy, Mason Breitzig, Lakshmi Galam, Ramani Soundararajan, Richard F Lockey, Narasaiah Kolliputi
Critically ill patients are commonly treated with high levels of oxygen, hyperoxia, for prolonged periods of time. Unfortunately, extended exposure to hyperoxia can exacerbate respiratory failure and lead to a high mortality rate. Mitochondrial A-kinase anchoring protein (Akap) has been shown to regulate mitochondrial function. It has been reported that, under hypoxic conditions, Akap121 undergoes proteolytic degradation and promotes cardiac injury. However, the role of Akap1 in hyperoxia-induced acute lung injury (ALI) is largely unknown...
February 1, 2018: American Journal of Physiology. Lung Cellular and Molecular Physiology
Bracy A Fertig, George S Baillie
cAMP is the archetypal and ubiquitous second messenger utilised for the fine control of many cardiovascular cell signalling systems. The ability of cAMP to elicit cell surface receptor-specific responses relies on its compartmentalisation by cAMP hydrolysing enzymes known as phosphodiesterases. One family of these enzymes, PDE4, is particularly important in the cardiovascular system, where it has been extensively studied and shown to orchestrate complex, localised signalling that underpins many crucial functions of the heart...
January 31, 2018: Journal of Cardiovascular Development and Disease
Katharina Schrade, Jessica Tröger, Adeeb Eldahshan, Kerstin Zühlke, Kamal R Abdul Azeez, Jonathan M Elkins, Martin Neuenschwander, Andreas Oder, Mohamed Elkewedi, Sarah Jaksch, Karsten Andrae, Jinliang Li, Joao Fernandes, Paul Markus Müller, Stephan Grunwald, Stephen F Marino, Tanja Vukićević, Jenny Eichhorst, Burkhard Wiesner, Marcus Weber, Michael Kapiloff, Oliver Rocks, Oliver Daumke, Thomas Wieland, Stefan Knapp, Jens Peter von Kries, Enno Klussmann
Stimulation of renal collecting duct principal cells with antidiuretic hormone (arginine-vasopressin, AVP) results in inhibition of the small GTPase RhoA and the enrichment of the water channel aquaporin-2 (AQP2) in the plasma membrane. The membrane insertion facilitates water reabsorption from primary urine and fine-tuning of body water homeostasis. Rho guanine nucleotide exchange factors (GEFs) interact with RhoA, catalyze the exchange of GDP for GTP and thereby activate the GTPase. However, GEFs involved in the control of AQP2 in renal principal cells are unknown...
2018: PloS One
Santosh V Suryavanshi, Shweta M Jadhav, Bradley K McConnell
A-kinase anchoring proteins (AKAPs) belong to a family of scaffolding proteins that bind to protein kinase A (PKA) by definition and a variety of crucial proteins, including kinases, phosphatases, and phosphodiesterases. By scaffolding these proteins together, AKAPs build a "signalosome" at specific subcellular locations and compartmentalize PKA signaling. Thus, AKAPs are important for signal transduction after upstream activation of receptors ensuring accuracy and precision of intracellular PKA-dependent signaling pathways...
January 25, 2018: Journal of Cardiovascular Development and Disease
Tanya A Baldwin, Carmen W Dessauer
Cyclic adenosine monophosphate (cAMP), synthesized by adenylyl cyclase (AC), is a universal second messenger that regulates various aspects of cardiac physiology from contraction rate to the initiation of cardioprotective stress response pathways. Local pools of cAMP are maintained by macromolecular complexes formed by A-kinase anchoring proteins (AKAPs). AKAPs facilitate control by bringing together regulators of the cAMP pathway including G-protein-coupled receptors, ACs, and downstream effectors of cAMP to finely tune signaling...
January 16, 2018: Journal of Cardiovascular Development and Disease
Cason R King, Steven F Gameiro, Tanner M Tessier, Ali Zhang, Joe S Mymryk
The E1A proteins of the various human adenovirus (HAdV) species perform the critical task of converting an infected cell into a setting primed for virus replication. While E1A proteins differ in both sequence and mechanism, the evolutionary pressure on viruses with limited coding capacity ensures that these proteins often have significant overlap in critical functions. HAdV-5 E1A is known to use mimicry to rewire cyclic AMP (cAMP) signaling by decoupling protein kinase A (PKA) from cellular A-kinase anchoring proteins (AKAPs) and utilizing PKA to its own advantage...
January 24, 2018: Journal of Virology
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
Anna Bieluszewska, Martyna Weglewska, Tomasz Bieluszewski, Krzysztof Lesniewicz, Elzbieta Poreba
The main function of the A kinase-anchoring proteins (AKAPs) is to target the cyclic AMP-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 histone H3 lysine 4 (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
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
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
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 Thr-286 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...
February 2, 2018: Journal of Biological Chemistry
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
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
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
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
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
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