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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...
April 1, 2017: Neuroscience
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
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
Raquel Guinzberg, Antonio Díaz-Cruz, Carlos Acosta-Trujillo, María Magdalena Vilchis-Landeros, Héctor Vázquez-Meza, Carlos Lozano-Flores, Natalia Chiquete-Felix, Alfredo Varela-Echavarría, Salvador Uribe-Carvajal, Héctor Riveros-Rosas, Enrique Piña
Spatiotemporal regulation of cAMP within the cell is required to achieve receptor-specific responses. The mechanism through which the cell selects a specific response to newly synthesized cAMP is not fully understood. In hepatocyte plasma membranes, we identified two functional and independent cAMP-responsive signaling protein macrocomplexes that produce, use, degrade, and regulate their own nondiffusible (sequestered) cAMP pool to achieve their specific responses. Each complex responds to the stimulation of an adenosine G protein-coupled receptor (Ado-GPCR), bound to either A2A or A2B , but not simultaneously to both...
November 19, 2016: FEBS Journal
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
Chong Han, Hirofumi Tomita, Takayoshi Ohba, Kimitaka Nishizaki, Yoshiki Ogata, Yasushi Matsuzaki, Daisuke Sawamura, Teruyuki Yanagisawa, Tomohiro Osanai, Tadaatsu Imaizumi, Atsushi Matsubara, Takeshi Adachi, Kyoichi Ono, Ken Okumura, Manabu Murakami
Genetic analyses have revealed an important association between A-kinase anchoring proteins (AKAPs) and the intracellular calcium modulating system. AKAP5, also known as AKAP79/150, is an anchoring protein between PKA and voltage-dependent calcium channels, ryanodine receptor-2, phospholamban and other molecules. The aim of the present study was to elucidate the physiological importance of AKAP5 in the creation of cardiac rhythm using AKAP5-null mice. ECG analysis showed a normal sinus rhythm and a decreased responsiveness to isoproterenol in AKAP5-null mice compared with wild-type mice...
January 22, 2016: Biochemical and Biophysical Research Communications
Hee Yeon Kay, Derek L Greene, Seungwoo Kang, Anastasia Kosenko, Naoto Hoshi
Valproic acid (VPA) has been widely used for decades to treat epilepsy; however, its mechanism of action remains poorly understood. Here, we report that the anticonvulsant effects of nonacute VPA treatment involve preservation of the M-current, a low-threshold noninactivating potassium current, during seizures. In a wide variety of neurons, activation of Gq-coupled receptors, such as the m1 muscarinic acetylcholine receptor, suppresses the M-current and induces hyperexcitability. We demonstrated that VPA treatment disrupts muscarinic suppression of the M-current and prevents resultant agonist-induced neuronal hyperexcitability...
October 1, 2015: Journal of Clinical Investigation
Amy S Bogard, Steven J Tavalin
PKMζ is generated via an alternative transcriptional start site in the atypical protein kinase C (PKC)ζ isoform, which removes N-terminal regulatory elements, including the inhibitory pseudosubstrate domain, consequently rendering the kinase constitutively active. Persistent PKMζ activity has been proposed as a molecular mechanism for the long-term maintenance of synaptic plasticity underlying some forms of memory. Many studies supporting a role for PKMζ in synaptic plasticity and memory have relied on the PKCζ pseudosubstrate-derived ζ-inhibitory peptide (ZIP)...
October 2015: Molecular Pharmacology
Kui Chen, Yu An, Lu Tie, Yan Pan, Xuejun Li
Now stimulation of AMPA receptor as well as its downstream pathways is considered as potential central mediators in antidepressant mechanisms. As a signal integrator which binds to AMPA receptor, A-kinase anchoring protein 79-(AKAP79-) PKA complex is regarded as a potential drug target to exert neuroprotective effects. A well-tolerated and multitarget drug curcumin has been confirmed to exert antidepressant-like effects. To explore whether AKAP79-PKA complex is involved in curcumin-mediated antiexcitotoxicity, we detected calcium signaling, subcellular location of AKAP79-PKA complex, phosphorylation of glutamate receptor, and ERK and AKT cascades...
2015: Evidence-based Complementary and Alternative Medicine: ECAM
Michael E Authement, Jayaraj N Kodangattil, Shawn Gouty, Milan Rusnak, Aviva J Symes, Brian M Cox, Fereshteh S Nugent
Adverse early-life experiences such as child neglect and abuse increase the risk of developing addiction and stress-related disorders through alterations in motivational systems including the mesolimbic dopamine (DA) pathway. Here we investigated whether a severe early-life stress (i.e., maternal deprivation, MD) promotes DA dysregulation through an epigenetic impairment of synaptic plasticity within ventral tegmental area (VTA) DA neurons. Using a single 24-hr episode of MD and whole-cell patch clamp recording in rat midbrain slices, we show that MD selectively induces long-term depression (LTD) and shifts spike timing-dependent plasticity (STDP) toward LTD at GABAergic synapses onto VTA DA neurons through epigenetic modifications of postsynaptic scaffolding A-kinase anchoring protein 79/150 (AKAP79/150) signaling...
June 3, 2015: Neuron
Ilse Delint-Ramirez, Debbie Willoughby, Gerald R V Hammond, Laura J Ayling, Dermot M F Cooper
No abstract text is available yet for this article.
May 22, 2015: Journal of Biological Chemistry
Bret K Samelson, Bryan B Gore, Jennifer L Whiting, Patrick J Nygren, Alicia M Purkey, Marcie Colledge, Lorene K Langeberg, Mark L Dell'Acqua, Larry S Zweifel, John D Scott
Anchoring proteins direct protein kinases and phosphoprotein phosphatases toward selected substrates to control the efficacy, context, and duration of neuronal phosphorylation events. The A-kinase anchoring protein AKAP79/150 interacts with protein kinase A (PKA), protein kinase C (PKC), and protein phosphatase 2B (calcineurin) to modulate second messenger signaling events. In a mass spectrometry-based screen for additional AKAP79/150 binding partners, we have identified the Roundabout axonal guidance receptor Robo2 and its ligands Slit2 and Slit3...
May 29, 2015: Journal of Biological Chemistry
Yanjing Guo, Tao Bo, Xinli Zhou, Ling Gao, Yong Wang, Jiajun Zhao
Kinase Anchoring Proteins (AKAPs) have evolved to regulate the spatial and temporal organization of cellular signal transduction. As a typical member, AKAP5 which consisting of three orthologues: bovine AKAP75, rodent AKAP150 and human AKAP79, is the best known model in the anchoring and targeting properties. It is shown that AKAP5 can bind β2-adrenergic receptor, which is a member of GPCR superfamily, and orchestrate the interactions of various protein kinases, protein phosphatases and cytoskeletal element...
2015: Neuro Endocrinology Letters
Jie Zhang, Mark S Shapiro
A-kinase anchoring proteins (AKAPs) have emerged as a converging point of diverse signals to achieve spatiotemporal resolution of directed cellular regulation. With the extensive studies of AKAP79/150 in regulation of ion channel activity, the major questions to be posed centre on the mechanism and functional role of synergistic regulation of ion channels by such signalling proteins. In this review, we summarize recent discoveries of AKAP79/150-mediated modulation of voltage-gated neuronal M-type (KCNQ, Kv7) K(+) channels and L-type CaV 1 Ca(2+) channels, on both short- and longer-term time scales, highlighting the dynamics of the macromolecular signalling complexes in brain and peripheral nerve We also discuss several models for the possible mechanisms of these multi-protein assemblies and how they serve the agenda of the neurons in which they occur...
January 1, 2016: Journal of Physiology
Kevin M Woolfrey, Jennifer L Sanderson, Mark L Dell'Acqua
Phosphorylation and dephosphorylation of AMPA-type ionotropic glutamate receptors (AMPARs) by kinases and phosphatases and interactions with scaffold proteins play essential roles in regulating channel biophysical properties and trafficking events that control synaptic strength during NMDA receptor-dependent synaptic plasticity, such as LTP and LTD. We previously demonstrated that palmitoylation of the AMPAR-linked scaffold protein A-kinase anchoring protein (AKAP) 79/150 is required for its targeting to recycling endosomes in dendrites, where it regulates exocytosis from these compartments that is required for LTP-stimulated enlargement of postsynaptic dendritic spines, delivery of AMPARs to the plasma membrane, and maintenance of synaptic potentiation...
January 14, 2015: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Jill L Thompson, Trevor J Shuttleworth
KEY POINTS: Although both the calcium store-dependent CRAC channels and the store-independent ARC channels are regulated by the protein STIM1, CRAC channels are regulated by STIM1 in the endoplasmic reticulum, whilst ARC channels are regulated by the STIM1 constitutively resident in the plasma membrane. We now demonstrate that activation of the ARC channels, but not CRAC channels, is uniquely dependent on phosphorylation of a single residue (T389) in the extensive cytosolic domain of STIM1 by protein kinase A...
February 1, 2015: Journal of Physiology
Shuang Qiu, Ming Zhang, Yan Liu, Yanyan Guo, Huan Zhao, Qian Song, Minggao Zhao, Richard L Huganir, Jianhong Luo, Hui Xu, Min Zhuo
Long-term potentiation of glutamatergic transmission has been observed after physiological learning or pathological injuries in different brain regions, including the spinal cord, hippocampus, amygdala, and cortices. The insular cortex is a key cortical region that plays important roles in aversive learning and neuropathic pain. However, little is known about whether excitatory transmission in the insular cortex undergoes plastic changes after peripheral nerve injury. Here, we found that peripheral nerve ligation triggered the enhancement of AMPA receptor (AMPAR)-mediated excitatory synaptic transmission in the insular cortex...
October 1, 2014: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
S Weninger, K Van Craenenbroeck, R T Cameron, F Vandeput, M A Movsesian, G S Baillie, R A Lefebvre
Phosphodiesterase (PDE) 3 and PDE4, which degrade cyclic adenosine monophosphate (cAMP), are important regulators of 5-hydroxytryptamine (5-HT) 4 receptor signaling in cardiac tissue. Therefore, we investigated whether they interact with the 5-HT4(b) receptor, and whether A-kinase anchoring proteins (AKAPs), scaffolding proteins that bind to the regulatory subunit of protein kinase A (PKA) and contribute to the spacial-temporal control of cAMP signaling, are involved in the regulation of 5-HT4(b) receptor signaling...
November 2014: Cellular Signalling
Pulak Kar, Krishna Samanta, Holger Kramer, Otto Morris, Daniel Bakowski, Anant B Parekh
NFAT-dependent gene expression is essential for the development and function of the nervous, immune, and cardiovascular systems and kidney, bone, and skeletal muscle. Most NFAT protein resides in the cytoplasm because of extensive phosphorylation, which masks a nuclear localization sequence. Dephosphorylation by the Ca(2+)-calmodulin-activated protein phosphatase calcineurin triggers NFAT migration into the nucleus. In some cell types, NFAT can be activated by Ca(2+) nanodomains near open store-operated Orai1 and voltage-gated Ca(2+) channels in the plasma membrane...
June 16, 2014: Current Biology: CB
Jonathan G Murphy, Jennifer L Sanderson, Jessica A Gorski, John D Scott, William A Catterall, William A Sather, Mark L Dell'Acqua
L-type voltage-gated Ca2+ channels (LTCC) couple neuronal excitation to gene transcription. LTCC activity is elevated by the cyclic AMP (cAMP)-dependent protein kinase (PKA) and depressed by the Ca2+-dependent phosphatase calcineurin (CaN), and both enzymes are localized to the channel by A-kinase anchoring protein 79/150 (AKAP79/150). AKAP79/150 anchoring of CaN also promotes LTCC activation of transcription through dephosphorylation of the nuclear factor of activated T cells (NFAT). We report here that the basal activity of AKAP79/150-anchored PKA maintains neuronal LTCC coupling to CaN-NFAT signaling by preserving LTCC phosphorylation in opposition to anchored CaN...
June 12, 2014: Cell Reports
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