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Adenylyl cyclases

David Agustin Leon-Navarro, Jose Luis Albasanz, Mairena Martin
G-protein coupled receptors are transmembrane proteins widely expressed in cells and their transduction pathways are mediated by controlling second messenger levels through different G-protein interactions. Many of these receptors have been described as involved in the physiopathology of neurodegenerative diseases and even considered as potential targets for the design of novel therapeutic strategies. Endogenous and synthetic allosteric and orthosteric selective ligands are able to modulate GPCRs at both gene and protein expression levels and can also modify their physiological function...
April 15, 2018: Current Neuropharmacology
Gergő Szanda, Éva Wisniewski, Anikó Rajki, András Spät
We have previously demonstrated in H295R adrenocortical cells that the Ca2+ -dependent production of intramitochondrial cAMP (mt-cAMP) by the matrix soluble adenylyl cyclase (sAC) is associated with enhanced aldosterone production. Now we examined whether mitochondrial sAC and mt-cAMP fine-tune mitochondrial Ca2+ metabolism to support steroidogenesis. Reduction of mt-cAMP formation resulted in decelerated mitochondrial Ca2+ accumulation in intact cells during K+ -induced Ca2+ signalling and also in permeabilised cells exposed to elevated perimitochondrial [Ca2+ ]...
April 16, 2018: Journal of Cell Science
Shoma Sato, Kohei Ueno, Minoru Saitoe, Takaomi Sakai
Synaptic plasticity has been studied to reveal the molecular and cellular mechanisms of associative and nonassociative learning. The fruit fly Drosophila melanogaster can be used to identify the molecular mechanisms of synaptic plasticity because vast genetic information or tools are available. Here, by ex vivo Ca2+ imaging of an isolated cultured Drosophila brain, we examined the novel activity-dependent synaptic depression between the projection neurons of the antennal lobe (AL) and mushroom body (MB). Ex vivo Ca2+ imaging analysis revealed that electrical stimulation of AL elicits Ca2+ responses in the dendritic (calyx) and axonal (α lobe) regions of MB neurons, and the responses are reduced after repetitive AL stimulation...
April 16, 2018: Journal of Physiology
Qi Hu, Kevan M Shokat
The single most frequent cancer-causing mutation across all heterotrimeric G proteins is R201C in Gαs. The current model explaining the gain-of-function activity of the R201 mutations is through the loss of GTPase activity and resulting inability to switch off to the GDP state. Here, we find that the R201C mutation can bypass the need for GTP binding by directly activating GDP-bound Gαs through stabilization of an intramolecular hydrogen bond network. Having found that a gain-of-function mutation can convert GDP into an activator, we postulated that a reciprocal mutation might disrupt the normal role of GTP...
April 1, 2018: Cell
Maxine J Roberts, Rebecca E Broome, Toby C Kent, Steven J Charlton, Elizabeth M Rosethorne
BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive fibrotic lung disease for which there is no cure. Current therapeutics are only able to slow disease progression, therefore there is a need to explore alternative, novel treatment options. There is increasing evidence that the 3', 5' cyclic adenosine monophosphate (cAMP) pathway is an important modulator in the development of fibrosis, with increasing levels of cAMP able to inhibit cellular processes associated with IPF...
April 7, 2018: Respiratory Research
Weiye Wang, Song Chen, Satarupa Das, Wolfgang Losert, Carole A Parent
Dictyostelium discoideum cells transport adenylyl cyclase A (ACA) containing vesicles to the back of polarized cells to relay exogenous cAMP signals during chemotaxis. Fluorescence in situ hybridization (FISH) experiments showed that ACA mRNA is also asymmetrically distributed at the back of polarized cells. Using the MS2 bacteriophage system, we now visualized the distribution of ACA mRNA in live chemotaxing cells. We found that the ACA mRNA localization is not dependent on the translation of the protein product and requires multiple cis-acting elements within the ACA coding sequence...
April 3, 2018: Journal of Cell Science
Raul M Luque, Rhonda D Kineman
Neuronostatin, a somatostatin gene-encoded peptide, exerts important physiological and metabolic actions in diverse tissues. However, the direct biological effects of neuronostatin on pituitary function of humans and primates are still unknown. This study used baboon (Papio anubis) primary pituitary cell cultures, a species that closely models human physiology, to demonstrate that neuronostatin inhibits basal, but not ghrelin-/GnRH-stimulated, GH and LH secretion in a dose- and time-dependent fashion, without affecting the secretion of other pituitary hormones (prolactin, ACTH, FSH, TSH) or changing mRNA levels...
April 3, 2018: Journal of Endocrinology
Ting Li, Nannan Liu
G-protein-coupled receptors (GPCRs) are a large family of seven-transmembrane domain proteins that exist in plants and animals, playing critical physiological functions through intracellular cascades. Previous studies revealed an important regulation pathway of GPCR/Guanine nucleotide-binding protein (G-protein)/Adenylyl Cyclase (AC)/cAMP-dependent protein kinase A (PKA) in the insecticide resistance and regulation of resistance-related P450 gene expression in highly resistant southern house mosquitoes, Culex quinquefasciatus Say (Diptera: Culicidae)...
March 28, 2018: Journal of Medical Entomology
Kim T Blackwell, Armando G Salinas, Parul Tewatia, Brad English, Jeanette Hellgren Kotaleski, David M Lovinger
The striatum, the input structure of the basal ganglia, is a major site of learning and memory for goal-directed actions and habit formation. Spiny projection neurons of the striatum integrate cortical, thalamic, and nigral inputs to learn associations, with cortico-striatal synaptic plasticity as a learning mechanism. Signaling molecules implicated in synaptic plasticity are altered in alcohol withdrawal, which may contribute to overly strong learning and increased alcohol seeking and consumption. To understand how interactions among signaling molecules produce synaptic plasticity, we implemented a mechanistic model of signaling pathways activated by dopamine D1 receptors, acetylcholine receptors, and glutamate...
March 30, 2018: European Journal of Neuroscience
Kelly E Bosse, Farhad Ghoddoussi, Ajay T Eapen, Jennifer L Charlton, Laura L Susick, Kirt Desai, Bruce A Berkowitz, Shane A Perrine, Alana C Conti
Evidence suggests a predictive link between elevated basal activity within reward-related networks (e.g., cortico-basal ganglia-thalamic networks) and vulnerability for alcoholism. Both calcium channel function and cyclic adenosine monophosphate (cAMP)/protein kinase A-mediated signaling are critical modulators of reward neurocircuitry and reward-related behaviors. Calcium/calmodulin-stimulated adenylyl cyclases (AC) 1 and 8 are sensitive to activity-dependent increases in intracellular calcium and catalyze cAMP production...
March 28, 2018: Brain Imaging and Behavior
Kaina Zhang, Ke Zeng, Congcong Shen, Shiyu Tian, Minghui Yang
The authors describe a fluorometric method for the determination of the activity and inhibition of protein kinase A (PKA). In the presence of ATP, PKA catalyzes the transfer of phosphate groups from ATP to a peptide, and the generated phosphorylated peptide quenches the fluorescence (measured at excitation/emission peaks of 340/440 nm) of the hydroxyapatite nanoparticles (HAP-NPs). A linear logarithmic relationship of PKA concentrations with fluorescence intensity in the range from 1 to 50 U·L-1 was obtained, and the lower limit of detection (LOD) is 0...
March 16, 2018: Mikrochimica Acta
Julia Bräunig, Juliane Dinter, Carolin S Höfig, Sarah Paisdzior, Michal Szczepek, Patrick Scheerer, Mark Rosowski, Jens Mittag, Gunnar Kleinau, Heike Biebermann
Trace amine-associated receptors (TAARs) belong to the class A G-protein-coupled receptors (GPCR) and are evolutionary related to aminergic receptors. TAARs have been identified to mediate effects of trace amines. TAAR1 signaling is mainly mediated via activation of the Gs /adenylyl cyclase pathway. In addition to classical trace amines, TAAR1 can also be activated by the thyroid hormone derivative 3-iodothyronamine (3-T1AM). Pharmacological doses of 3-T1AM induced metabolic and anapyrexic effects, which might be centrally mediated in the hypothalamus in rodents...
2018: Frontiers in Pharmacology
Gemma Navarro, Arnau Cordomí, Verónica Casadó-Anguera, Estefanía Moreno, Ning-Sheng Cai, Antoni Cortés, Enric I Canela, Carmen W Dessauer, Vicent Casadó, Leonardo Pardo, Carme Lluís, Sergi Ferré
G protein-coupled receptors (GPCRs), G proteins and adenylyl cyclase (AC) comprise one of the most studied transmembrane cell signaling pathways. However, it is unknown whether the ligand-dependent interactions between these signaling molecules are based on random collisions or the rearrangement of pre-coupled elements in a macromolecular complex. Furthermore, it remains controversial whether a GPCR homodimer coupled to a single heterotrimeric G protein constitutes a common functional unit. Using a peptide-based approach, we here report evidence for the existence of functional pre-coupled complexes of heteromers of adenosine A2A receptor and dopamine D2 receptor homodimers coupled to their cognate Gs and Gi proteins and to subtype 5 AC...
March 28, 2018: Nature Communications
Thomas Pleli, Antonia Mondorf, Nerea Ferreiros, Dominique Thomas, Karel Dvorak, Ricardo M Biondi, Dagmar Meyer Zu Heringdorf, Stefan Zeuzem, Gerd Geisslinger, Herbert Zimmermann, Oliver Waidmann, Albrecht Piiper
BACKGROUND/AIMS: Signaling of Gs protein-coupled receptors (GsPCRs) is accomplished by stimulation of adenylyl cyclase, causing an increase of the intracellular cAMP concentration, activation of the intracellular cAMP effectors protein kinase A (PKA) and Epac, and an efflux of cAMP, the function of which is still unclear. METHODS: Activation of adenylyl cyclase by GsPCR agonists or cholera toxin was monitored by measurement of the intracellular cAMP concentration by ELISA, anti-phospho-PKA substrate motif phosphorylation by immunoblotting, and an Epac-FRET assay in the presence and absence of adenosine receptor antagonists or ecto-nucleotide phosphodiesterase/pyrophosphatase2 (eNPP2) inhibitors...
March 27, 2018: Cellular Physiology and Biochemistry
Yi-Hui Shen, Xi-Ru Chen, Chun-Xi Yang, Bo-Xun Liu, Peng Li
Alamandine is a newly discovered new component of the renin-angiotensin (Ang) system (RAS) that has been shown to exert vasoactive effects in some areas of the nervous system. The present study investigated whether administration of alamandine to the hypothalamic paraventricular nucleus (PVN) modulates blood pressure and sympathetic activity. Mean arterial pressure (MAP) and renal sympathetic nerve activity (RSNA) were recorded in anaesthetized rats. PVN microinjection of alamandine increased MAP and RSNA both in Wistar-Kyoto (WKY) rats and in spontaneously hypertensive rats (SHRs), but to a greater extent in SHRs...
March 23, 2018: Peptides
Souvik Dey, Suranjana Goswami, Alaa Eisa, Rahul Bhattacharjee, Cameron Brothag, Douglas Kline, Srinivasan Vijayaraghavan
The multifaceted glycogen synthase kinase (GSK3) has an essential role in sperm and male fertility. Since cyclic AMP (cAMP) plays an important role in sperm function, we investigated whether GSK3 and cAMP pathways may be interrelated. We used GSK3 and soluble adenylyl cyclase (sAC) knockout mice and pharmacological modulators to examine this relationship. Intracellular cAMP levels were found to be significantly lower in sperm lacking GSK3α or GSK3β. A similar outcome was observed when sperm cells were treated with SB216763, a GSK3 inhibitor...
March 25, 2018: Journal of Cellular Physiology
Xiaojiao Guo, Zongyuan Ma, Baozhen Du, Ting Li, Wudi Li, Lingling Xu, Jing He, Le Kang
Dopamine receptor 1 (Dop1) mediates locust attraction behaviors, however, the mechanism by which Dop1 modulates this process remains unknown to date. Here, we identify differentially expressed small RNAs associated with locust olfactory attraction after activating and inhibiting Dop1. Small RNA transcriptome analysis and qPCR validation reveal that Dop1 activation and inhibition downregulates and upregulates microRNA-9a (miR-9a) expression, respectively. miR-9a knockdown in solitarious locusts increases their attraction to gregarious volatiles, whereas miR-9a overexpression in gregarious locusts reduces olfactory attraction...
March 22, 2018: Nature Communications
Rafael V M Manalo, Paul M B Medina
Previous studies have suggested that caffeine reduces the risk of L-DOPA-induced dyskinesia. However, caffeine is also known to promote dopamine signaling, which seemingly contradicts this observed effect. To this end, the study aimed to clarify the mechanism of caffeine neuroprotection in vivo when excess dopamine is present. Transgenic Caenorhabditis elegans (UA57) overproducing dopamine was exposed to caffeine for 7 days and monitored by observing GFP-tagged dopaminergic (DA) neurons via fluorescence microscopy...
2018: Frontiers in Neuroscience
Marta Sánchez-Soto, Verònica Casadó-Anguera, Hideaki Yano, Brian Joseph Bender, Ning-Sheng Cai, Estefanía Moreno, Enric I Canela, Antoni Cortés, Jens Meiler, Vicent Casadó, Sergi Ferré
The poor norepinephrine innervation and high density of Gi/o-coupled α2A - and α2C -adrenoceptors in the striatum and the dense striatal dopamine innervation have prompted the possibility that dopamine could be an effective adrenoceptor ligand. Nevertheless, the reported adrenoceptor agonistic properties of dopamine are still inconclusive. In this study, we analyzed the binding of norepinephrine, dopamine, and several compounds reported as selective dopamine D2 -like receptor ligands, such as the D3 receptor agonist 7-OH-PIPAT and the D4 receptor agonist RO-105824, to α2 -adrenoceptors in cortical and striatal tissue, which express α2A -adrenoceptors and both α2A - and α2C -adrenoceptors, respectively...
March 18, 2018: Molecular Neurobiology
Shunsuke Shiina, Ayaka Kanemura, Chihiro Suzuki, Fumiko Yamaki, Keisuke Obara, Daisuke Chino, Yoshio Tanaka
Object We identified the β-adrenoceptor (β-AR) subtypes responsible for the relaxant responses to adrenaline (AD) and noradrenaline (NA) in the rat thoracic aorta and examined the role of cAMP which is involved in these relaxant responses. Methods The effects of β-AR antagonists or the adenylyl cyclase inhibitor SQ 22,536 on AD- and NA-induced relaxant responses in phenylephrine-induced contraction and increases in cAMP levels were examined in isolated, endothelium-denuded rat thoracic aorta segments. Results AD-induced relaxation was completely suppressed by propranolol (10-7  M) or by ICI-118,551 (10-8  M) plus atenolol (10-6 M), and was also very strongly inhibited by ICI-118,551 (10-8  M) alone...
2018: Journal of Smooth Muscle Research, Nihon Heikatsukin Gakkai Kikanshi
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