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Adenylyl cyclases

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https://www.readbyqxmd.com/read/28805209/neuropeptide-s-induces-acute-anxiolysis-by-phospholipase-c-dependent-signaling-within-the-medial-amygdala
#1
Thomas Grund, Inga D Neumann
Neuropeptide S (NPS) is an important anxiolytic substance of the brain. However, the signaling pathways downstream of NPS receptor (NPSR) activation, underlying the behavioral effect of NPS, remain largely unknown. Here, we show that bilateral microinfusion of NPS (0.2 nmol/0.5 μl) into the medial amygdala (MeA) of male adult Wistar rats reduced anxiety-related behavior on both, the elevated plus-maze and the open field. Moreover, as shown in amygdala tissue micropunches intracerebroventricular infusion of NPS (1 nmol/5 μl) I) evoked phosphorylation and synthesis of CaMKIIɑ in relation to reference protein beta-tubulin representing Ca(2+) influx, and II) induced phosphorylation of mitogen-activated protein kinase ERK1/2...
August 14, 2017: Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology
https://www.readbyqxmd.com/read/28767701/cardiac-directed-expression-of-a-catalytically-inactive-adenylyl-cyclase-6-protects-the-heart-from-sustained-%C3%AE-adrenergic-stimulation
#2
Mei Hua Gao, N Chin Lai, Dimosthenis Giamouridis, Young Chul Kim, Tracy Guo, H Kirk Hammond
OBJECTIVES: Increased expression of adenylyl cyclase type 6 (AC6) has beneficial effects on the heart through cyclic adenosine monophosphate (cAMP)-dependent and cAMP-independent pathways. We previously generated a catalytically inactive mutant of AC6 (AC6mut) that has an attenuated response to β-adrenergic receptor stimulation, and, consequently, exhibits reduced myocardial cAMP generation. In the current study we test the hypothesis that cardiac-directed expression of AC6mut would protect the heart from sustained β-adrenergic receptor stimulation, a condition frequently encountered in patients with heart failure...
2017: PloS One
https://www.readbyqxmd.com/read/28750036/generation-and-phenotypic-characterization-of-pde1a-mutant-mice
#3
Xiaofang Wang, Satsuki Yamada, Wells B LaRiviere, Hong Ye, Jason L Bakeberg, María V Irazabal, Fouad T Chebib, Jan van Deursen, Peter C Harris, Caroline R Sussman, Atta Behfar, Christopher J Ward, Vicente E Torres
It has been proposed that a reduction in intracellular calcium causes an increase in intracellular cAMP and PKA activity through stimulation of calcium inhibitable adenylyl cyclase 6 and inhibition of phosphodiesterase 1 (PDE1), the main enzymes generating and degrading cAMP in the distal nephron and collecting duct, thus contributing to the development and progression of autosomal dominant polycystic kidney disease (ADPKD). In zebrafish pde1a depletion aggravates and overexpression ameliorates the cystic phenotype...
2017: PloS One
https://www.readbyqxmd.com/read/28747357/an-inhibitor-of-histone-deacetylase-6-activity-acy-1215-reduces-camp-and-cyst-growth-in-polycystic-kidney-disease
#4
Murali Krishna Yanda, Qiangni Liu, Liudmila Cebotaru
Adult-onset autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in either the PKD1 or PKD2 gene, leading to malfunction of their gene products, polycystin 1 or 2. Histone deacetylase 6 (HDAC6) expression and activity are increased in PKD1-mutant renal epithelial cells. Here we studied the effect of ACY-1215, a specific HDAC6 inhibitor, on cyst growth in ADPKD. Treatment with ACY-1215 slowed cyst growth in a mouse model of ADPKD that forms massive cysts within 3 weeks after knockout of polycystin 1 function...
July 26, 2017: American Journal of Physiology. Renal Physiology
https://www.readbyqxmd.com/read/28734766/trpv1-modulates-morphine-induced-conditioned-place-preference-via-p38-mapk-in-the-nucleus-accumbens
#5
Sa-Ik Hong, Thi-Lien Nguyen, Shi-Xun Ma, Hyoung-Chun Kim, Seok-Yong Lee, Choon-Gon Jang
Emerging evidence suggests that the transient receptor potential vanilloid type 1 channel (TRPV1) is a novel target for the treatment of drug addiction, such as cocaine and morphine. Previously we reported that TRPV1 inhibition reduced morphine reward in the dorsal striatum (DSt) of mice and morphine self-administration through a decrease in accumbal activity in rats. However, the role of TRPV1 on morphine-conditioned reward in addiction-related brain regions, such as the nucleus accumbens (NAc), has not been previously established...
July 19, 2017: Behavioural Brain Research
https://www.readbyqxmd.com/read/28734062/coumarins-and-adenosine-receptors-new-perceptions-in-structure-affinity-relationships
#6
André Fonseca, Maria João Matos, Santiago Vilar, Sonja Kachler, Karl-Norbert Klotz, Eugenio Uriarte, Fernanda Borges
Adenosine receptors (ARs) subtypes are involved in several physiological and pharmacological processes. Ligands able to selectively modulate one receptor subtype can delay or slow down the progression of diverse diseases. In this context, our research group focused its investigation into the discovery and development of novel, potent and selective ARs ligands based on coumarin scaffold. Therefore, a series 3-phenylcarboxamidocoumarins were synthesised and their affinity for the human ARs subtypes was screened by radioligand binding assays for A1 , A2A and A3 receptors and for A2B by adenylyl cyclase assay...
July 22, 2017: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/28731589/effects-of-nitric-oxide-on-large-conductance-ca-2-activated-k-currents-in-human-cardiac-fibroblasts-through-pka-and-pkg-related-pathways
#7
Hyemi Bae, Inja Lim
The human cardiac fibroblast (HCF) is the most abundant cell type in the myocardium, and HCFs play critical roles in maintaining normal cardiac function. However, unlike cardiomyocytes, the electrophysiology of HCFs is not well established. In the cardiovascular system, Ca(2+) -activated K(+) (KCa) channels have distinct physiological and pathological functions, and nitric oxide (NO) play key roles. In this study, we investigated the potential effects of NO on KCa channels in HCFs. We recorded strong oscillating, well-maintained outward K(+) currents without marked inactivation throughout the test pulse period and detected outward rectification in the I-V curve; these are all characteristics that are typical of KCa currents...
July 21, 2017: Clinical and Experimental Pharmacology & Physiology
https://www.readbyqxmd.com/read/28727179/overexpression-of-g%C3%AE-s-in-murine-osteoblasts-in-vivo-leads-to-increased-bone-mass-and-decreased-bone-quality
#8
Lucia Zhang, Kim S Sugamori, Colin Claridge, Ariana Dela Cruz, Marc D Grynpas, Jane Mitchell
GαS is a heterotrimeric G protein that transduces signals from activated G protein-coupled receptors on the cell surface to stimulate adenylyl cyclase/cyclic adenosine monophosphate (AMP) signaling. GαS plays a central role in mediating numerous growth and maintenance processes including osteogenesis and bone turnover. Decreased GαS expression or activating mutations in GαS both affect bone, suggesting that modulating GαS protein levels may be important for bone health and development. To examine the effects of increased osteoblastic GαS expression on bone development in vivo, we generated transgenic mice with GαS overexpression in osteoblasts (HOM-Gs mice) driven by the 3...
July 20, 2017: Journal of Bone and Mineral Research: the Official Journal of the American Society for Bone and Mineral Research
https://www.readbyqxmd.com/read/28721398/calcium-stimulated-adenylyl-cyclase-subtype-1-ac1-contributes-to-ltp-in-the-insular-cortex-of-adult-mice
#9
Manabu Yamanaka, Takanori Matsuura, Haili Pan, Min Zhuo
Long-term potentiation (LTP) of synaptic transmission in the central nervous system is a key form of cortical plasticity. The insular cortex (IC) is known to play important roles in pain perception, aversive memory and mood disorders. LTP has been recently reported in the IC, however, the signaling pathway for IC LTP remains unknown. Here, we investigated the synaptic mechanism of IC LTP. We found that IC LTP induced by the pairing protocol was N-methyl-D-aspartate receptors (NMDARs) dependent, and expressed postsynaptically, since paired-pulse ratio (PPR) was not affected...
July 2017: Heliyon
https://www.readbyqxmd.com/read/28717253/prostacyclin-reverses-platelet-stress-fibre-formation-causing-platelet-aggregate-instability
#10
M Z Yusuf, Z Raslan, L Atkinson, A Aburima, S G Thomas, K M Naseem, S D J Calaminus
Prostacyclin (PGI2) modulates platelet activation to regulate haemostasis. Evidence has emerged to suggest that thrombi are dynamic structures with distinct areas of differing platelet activation. It was hypothesised that PGI2 could reverse platelet spreading by actin cytoskeletal modulation, leading to reduced capability of platelet aggregates to withstand a high shear environment. Our data demonstrates that post-flow of PGI2 over activated and spread platelets on fibrinogen, identified a significant reduction in platelet surface area under high shear...
July 17, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28717248/loss-of-type-9-adenylyl-cyclase-triggers-reduced-phosphorylation-of-hsp20-and-diastolic-dysfunction
#11
Yong Li, Tanya A Baldwin, Yan Wang, Janani Subramaniam, Anibal Garza Carbajal, Cameron S Brand, Shane R Cunha, Carmen W Dessauer
Adenylyl cyclase type 9 (AC9) is found tightly associated with the scaffolding protein Yotiao and the IKs ion channel in heart. But apart from potential IKs regulation, physiological roles for AC9 are unknown. We show that loss of AC9 in mice reduces less than 3% of total AC activity in heart but eliminates Yotiao-associated AC activity. AC9(-/-) mice exhibit no structural abnormalities but show a significant bradycardia, consistent with AC9 expression in sinoatrial node. Global changes in PKA phosphorylation patterns are not altered in AC9(-/-) heart, however, basal phosphorylation of heat shock protein 20 (Hsp20) is significantly decreased...
July 17, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28706453/mdl-12330a-potentiates-trail-induced-apoptosis-in-gastric-cancer-cells-through-chop-mediated-dr5-upregulation
#12
Sung-Chul Lim, Song Iy Han
MDL-12330A is a widely used adenylyl cyclase (AC) inhibitor that blocks AC/cAMP signaling. In this study, we demonstrated a novel antitumor activity of this drug in gastric carcinoma (GC) cell lines. In these GC cells, MDL-12330A reduced cell viability and induced cell death in a concentration-dependent manner. At a moderate concentration (~20 µM), MDL-12330A mainly induced apoptotic death whereas at concentrations greater than 20 µM, it increased non-apoptotic cell death. The induction of apoptosis was at least partially regulated by CHOP-mediated DR5 upregulation, as detected by immunoblotting and gene interference assays...
July 2017: Korean Journal of Physiology & Pharmacology
https://www.readbyqxmd.com/read/28701538/differential-expression-of-long-term-potentiation-among-identified-inhibitory-inputs-to-dopamine-neurons
#13
DeNard V Simmons, Alyssa K Petko, Carlos Antonio Paladini
The in vivo firing pattern of ventral tegmental area (VTA) dopamine neurons is controlled by GABA afferents originating primarily from the nucleus accumbens (NAc), rostromedial tegmental nucleus (RMTg), and from local GABA neurons within the VTA. Although different forms of plasticity have been observed from GABA inputs to VTA dopamine neurons - one dependent on cyclic GMP synthesis, the other dependent on adenylyl cyclase activation - it is unknown whether plasticity is differentially expressed in each. Using an optogenetic strategy, we show that identified inhibitory postsynaptic currents (IPSCs) from local VTA GABA neurons and NAc afferents exhibit a cyclic GMP-dependent long-term potentiation (LTP) that is capable of inhibiting the firing activity of dopamine neurons...
July 12, 2017: Journal of Neurophysiology
https://www.readbyqxmd.com/read/28696284/caffeine-induces-gastric-acid-secretion-via-bitter-taste-signaling-in-gastric-parietal-cells
#14
Kathrin Ingrid Liszt, Jakob Peter Ley, Barbara Lieder, Maik Behrens, Verena Stöger, Angelika Reiner, Christina Maria Hochkogler, Elke Köck, Alessandro Marchiori, Joachim Hans, Sabine Widder, Gerhard Krammer, Gareth John Sanger, Mark Manuel Somoza, Wolfgang Meyerhof, Veronika Somoza
Caffeine, generally known as a stimulant of gastric acid secretion (GAS), is a bitter-tasting compound that activates several taste type 2 bitter receptors (TAS2Rs). TAS2Rs are expressed in the mouth and in several extraoral sites, e.g., in the gastrointestinal tract, in which their functional role still needs to be clarified. We hypothesized that caffeine evokes effects on GAS by activation of oral and gastric TAS2Rs and demonstrate that caffeine, when administered encapsulated, stimulates GAS, whereas oral administration of a caffeine solution delays GAS in healthy human subjects...
July 25, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28686538/differential-intraocular-pressure-measurements-by-tonometry-and-direct-cannulation-after-treatment-with-soluble-adenylyl-cyclase-inhibitors
#15
Jarel K Gandhi, Uttio Roy Chowdhury, Zahid Manzar, Jochen Buck, Lonny R Levin, Michael P Fautsch, Alan D Marmorstein
PURPOSE: To validate the increase in intraocular pressure (IOP) caused by soluble adenylyl cyclase (sAC) inhibitors and determine reasons behind variation in IOP measurements performed by tonometry. METHODS: C57BL/6J mice were administered DMSO solubilized sAC inhibitors (KH7 or LRE-1) by intraperitoneal injection. Two hours post-treatment, mice were anesthetized with avertin or ketamine/xylazine/acepromazine (KXA). IOP was measured by a rebound tonometer or direct cannulation of the anterior chamber...
July 7, 2017: Journal of Ocular Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28682469/a3-adenosine-receptors-as-modulators-of-inflammation-from-medicinal-chemistry-to-therapy
#16
REVIEW
Kenneth A Jacobson, Stefania Merighi, Katia Varani, Pier Andrea Borea, Stefania Baraldi, Mojgan Aghazadeh Tabrizi, Romeo Romagnoli, Pier Giovanni Baraldi, Antonella Ciancetta, Dilip K Tosh, Zhan-Guo Gao, Stefania Gessi
The A3 adenosine receptor (A3 AR) subtype is a novel, promising therapeutic target for inflammatory diseases, such as rheumatoid arthritis (RA) and psoriasis, as well as liver cancer. A3 AR is coupled to inhibition of adenylyl cyclase and regulation of mitogen-activated protein kinase (MAPK) pathways, leading to modulation of transcription. Furthermore, A3 AR affects functions of almost all immune cells and the proliferation of cancer cells. Numerous A3 AR agonists, partial agonists, antagonists, and allosteric modulators have been reported, and their structure-activity relationships (SARs) have been studied culminating in the development of potent and selective molecules with drug-like characteristics...
July 6, 2017: Medicinal Research Reviews
https://www.readbyqxmd.com/read/28677151/getting-a-tan-without-getting-sik
#17
John D'Orazio
It has been more than a decade since the Fisher lab reported that epidermal eumelanin could be robustly up-regulated by topical application of forskolin, an adenylyl cyclase activator that bypassed a defective melanocortin 1 receptor (Mc1r) to promote melanin synthesis. Eumelanin induction protected fair-skinned mice from UV damage using an animal model that recapitulates many of the features of pigmented human epidermis. Through constitutive production of stem cell factor (Kit ligand) in the basal epidermis, the K14-Scf transgenic mouse retains interfollicular melanocytes in the skin and therefore accumulates melanin pigments in the epidermis...
July 5, 2017: Pigment Cell & Melanoma Research
https://www.readbyqxmd.com/read/28676923/biochemical-and-pharmacological-role-of-a1-adenosine-receptors-and-their-modulation-as-novel-therapeutic-strategy
#18
Katia Varani, Fabrizio Vincenzi, Stefania Merighi, Stefania Gessi, Pier Andrea Borea
Adenosine, the purine nucleoside, mediates its effects through activation of four G-protein coupled adenosine receptors (ARs) named as A1, A2A, A2B and A3. In particular, A1ARs are distributed through the body, primarily inhibitory in the regulation of adenylyl cyclase activity and able to reduce the cyclic AMP levels. Considerable advances have been made in the pharmacological and molecular characterization of A1ARs, which had been proposed as targets for the discovery and drug design of antagonists, agonists and allosteric enhancers...
July 5, 2017: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/28670631/cardiac-directed-expression-of-adenylyl-cyclase-catalytic-domain-reverses-cardiac-dysfunction-caused-by-sustained-beta-adrenergic-receptor-stimulation
#19
Mei Hua Gao, N Chin Lai, Dimosthenis Giamouridis, Young Chul Kim, Zhen Tan, Tracy Guo, Wolfgang H Dillmann, Jorge Suarez, H Kirk Hammond
OBJECTIVE: To test the hypothesis that cardiac-directed expression of the cytoplasmic domains of adenylyl cyclase-6 (AC6) would have beneficial effects on the heart. BACKGROUND: Eliminating the two transmembrane domains of AC6 yields a protein with an intact catalytic domain that is disengaged from membrane-associated β-adrenergic receptor stimulation, but with enhanced propensity for intracellular interactions. METHODS: We constructed a peptide of the C1 and C2 segments of AC6 (C1C2), expressed C1C2 in an adenovirus vector and generated transgenic lines with cardiac-directed C1C2 expression, which underwent sustained isoproterenol (Iso) infusion...
December 2016: JACC. Basic to Translational Science
https://www.readbyqxmd.com/read/28660299/physiological-crosstalk-between-the-ac-pka-and-plc-pkc-pathways-modulates-melatonin-mediated-monochromatic-light-induced-proliferation-of-t-lymphocytes-in-chickens
#20
Qingyun Guo, Zixu Wang, Yulan Dong, Jing Cao, Yaoxing Chen
Previous study has demonstrated that melatonin plays a critical role in monochromatic-light-induced lymphocyte proliferation in response to T cell mitogen concanavalin A (ConA). However, its intracellular mechanism is still unclear. In this study, we investigate the intracellular signal pathways of melatonin receptor-mediated T-lymphocyte proliferation in the spleens of chicks exposed to different light wavelengths. Results showed that green light enhanced T-lymphocyte proliferation by 2.46-6.83% and increased splenic mRNA and protein expressions of melatonin receptor subtypes (Mel1a, Mel1b and Mel1c) by 16...
June 28, 2017: Cell and Tissue Research
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