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Adenylyl cyclases

Kenji Suita, Takayuki Fujita, Wenqian Cai, Yuko Hidaka, Huiling Jin, Rajesh Prajapati, Masanari Umemura, Utako Yokoyama, Motohiko Sato, Björn C Knollmann, Satoshi Okumura, Yoshihiro Ishikawa
Sympathetic activation causes clinically important arrhythmias including atrial fibrillation (AF) and ventricular tachyarrhythmia. Although the usefulness of β-adrenergic receptor blockade therapy is widely accepted, its multiple critical side effects often prevent its initiation or continuation. The aim of this study is to determine the advantages of vidarabine, an adenylyl cyclase (AC)-targeted anti-sympathetic agent, as an alternative treatment for arrhythmia. We found that vidarabine, which we identified as a cardiac AC inhibitor, consistently shortens AF duration and reduces the incidence of sympathetic activation-induced ventricular arrhythmias...
February 16, 2018: Pflügers Archiv: European Journal of Physiology
Vincent Baggett, Aditi Mishra, Abigail L Kehrer, Abbey O Robinson, Paul Shaw, Troy Zars
Animals in a natural environment confront many sensory cues. Some of these cues bias behavioral decisions independent of experience, and action selection can reveal a stimulus-response (S-R) connection. However, in a changing environment it would be a benefit for an animal to update behavioral action selection based on experience, and learning might modify even strong S-R relationships. How animals use learning to modify S-R relationships is a largely open question. Three sensory stimuli, air, light, and gravity sources were presented to individual Drosophila melanogaster in both naïve and place conditioning situations...
March 2018: Learning & Memory
David L Gray, John A Allen, Scot Mente, Rebecca E O'Connor, George J DeMarco, Ivan Efremov, Patrick Tierney, Dmitri Volfson, Jennifer Davoren, Edward Guilmette, Michelle Salafia, Rouba Kozak, Michael D Ehlers
Selective activation of dopamine D1 receptors (D1Rs) has been pursued for 40 years as a therapeutic strategy for neurologic and psychiatric diseases due to the fundamental role of D1Rs in motor function, reward processing, and cognition. All known D1R-selective agonists are catechols, which are rapidly metabolized and desensitize the D1R after prolonged exposure, reducing agonist response. As such, drug-like selective D1R agonists have remained elusive. Here we report a novel series of selective, potent non-catechol D1R agonists with promising in vivo pharmacokinetic properties...
February 14, 2018: Nature Communications
Wanze Tang, Weilie Ma, Hang Ding, Margarita Lin, Le Xiang, Guorong Lin, Zhizhen Zhang
HDL apolipoprotein A-1-mediated cholesterol efflux pathway requires multiple cellular proteins and signal transduction pathways, including adenylyl cyclase (AC) / cAMP signaling. Due to the existence of multiple transmembrane AC isoforms, it was not known how many AC isoforms are expressed and which ones are essential for cholesterol efflux in macrophage foam cells. These questions were investigated in THP-1 macrophages in this study. QRT-PCR detected mRNAs for all nine transmembrane AC isoforms, but only the mRNA and protein of AC1 isoform were consistently upregulated by cholesterol loading and apoA-1...
February 14, 2018: Journal of Lipid Research
Manjari Rain, Himanshi Chaudhary, Ritushree Kukreti, Tashi Thinlas, Ghulam Mohammad, Qadar Pasha
Rain, Manjari, Himanshi Chaudhary, Ritushree Kukreti, Tashi Thinlas, Ghulam Mohammad, and Qadar Pasha. Elevated Vasodilatory Cyclases and Shorter Telomere Length Contribute to High-Altitude Pulmonary Edema. High Alt Med Biol. 00:000-000, 2018. AIM: High-altitude (HA) genetics is complex with respect to health and disease (HA pulmonary edema i.e., HAPE). Based on the widely recognized fact that oxidative stress is a major trigger of several physiological processes, this study was designed to establish the significance of vasodilatory cyclases and telomere length in HA physiology...
February 14, 2018: High Altitude Medicine & Biology
Wenli Feng, Jing Yang, Lu Yang, Qing Li, Xin Zhu, Zhiqin Xi, Zusha Qiao, Wen Cen
The aim of the present study was to investigate the association between Mrr1, adenylyl cyclase-associated protein 1 (Cap1) and multi-drug resistance gene 1 (MDR1), and to assess the mutations in Mrr1 and Cap1 in azole-resistant Candida albicans strains. The study isolated 68 C. albicans strains from patients with vulvovaginal candidiasis. Drug susceptibility testing was conducted to characterize the resistance profile of these strains to fluconazole, itraconazole and voriconazole. Polymerase chain reaction (PCR) amplification was performed for Cap1 and Mrr1, and the PCR products were sequenced to identify any mutations...
February 2018: Experimental and Therapeutic Medicine
Tatyana Veremeyko, Amanda W Y Yung, Marina Dukhinova, Inna S Kuznetsova, Igor Pomytkin, Alexey Lyundup, Tatyana Strekalova, Natasha S Barteneva, Eugene D Ponomarev
Although it has been demonstrated that cAMP pathway affect both adaptive and innate cell functions, the role of this pathway in the regulation of T-cell-mediated central nervous system (CNS) autoimmune inflammation, such as in experimental autoimmune encephalomyelitis (EAE), remains unclear. It is also unclear how cAMP pathway affects the function of CD4 T cells in vivo at the site of inflammation. We found that adenylyl cyclase activator Forskolin besides inhibition of functions autoimmune CD4 T cells also upregulated microRNA (miR)-124 in the CNS during EAE, which is associated with M2 phenotype of microglia/macrophages...
2018: Frontiers in Immunology
Biao Wang, Teng Chen, Jing Wang, Yuwei Jia, Huixun Ren, Feng Wu, Mei Hu, Yanjiong Chen
Methamphetamine (METH) elicits neuroinflammatory effects that may implicate its regulatory role on the microglial immune response. However, the mechanism underlying this remains unclear. In the present study, the effects of METH on lipopolysaccharide (LPS)-induced interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) productions were tested in BV-2 cells and primary microglial cells. Additionally, western blot analysis was used to examine the phosphorylation of mitogenactivated protein kinases (MAPKs)...
January 29, 2018: International Immunopharmacology
Hongliang Li, Sung Eun Shin, Mi Seon Seo, Jin Ryeol An, Il-Whan Choi, Won-Kyo Jung, Amy L Firth, Dae-Sung Lee, Mi-Jin Yim, Grace Choi, Jeong Min Lee, Sung Hun Na, Won Sun Park
AIM: Considering the clinical efficacy of dapagliflozin in patients with type 2 DM and the pathophysiological relevance of Kv channels for vascular reactivity. We investigate the vasodilatory effect of dapagliflozin and related mechanisms using phenylephrine (Phe)-induced contracted aortic rings. MATERIAL AND METHODS: Arterial tone measurement was performed in aortic smooth muscle. KEY FINDINGS: Application of dapagliflozin induced vasodilation in a concentration-dependent manner...
January 31, 2018: Life Sciences
Alessandra Porcu, Miriam Melis, Rostislav Turecek, Celine Ullrich, Ignazia Mocci, Bernhard Bettler, Gian Luigi Gessa, M Paola Castelli
Rimonabant is a potent and selective cannabinoid CB1 receptor antagonist widely used in animal and clinical studies. Besides its antagonistic properties, numerous studies have shown that, at micromolar concentrations rimonabant behaves as an inverse agonist at CB1 receptors. The mechanism underpinning this activity is unclear. Here we show that micromolar concentrations of rimonabant inhibited Gαi/o-type G proteins, resulting in a receptor-independent block of G protein signaling. Accordingly, rimonabant decreased basal and agonist stimulated [35S]GTPγS binding to cortical membranes of CB1- and GABAB-receptor KO mice and Chinese Hamster Ovary (CHO) cell membranes stably transfected with GABAB or D2 dopamine receptors...
January 27, 2018: Neuropharmacology
Meenakshi Tanwar, Komal Sharma, Preeti Moar, Suneel Kateriya
Cyclic nucleotide, such as cyclic GMP, is a secondary messenger that regulates a wide range of biological process via the diverse signaling cascades. Photoactivated adenylyl cyclases (PACs), constituted of blue light utilizing flavin (BLUF) and cyclase homology domain (CHD), are used as an optogenetic tool to modulate the cyclic AMP (cAMP) level and to study cAMP-mediated signal transduction mechanisms. Here, we have engineered photoactivated adenylyl cyclases (PACs) from microbes to photoactivated guanylyl cyclases (PGCs) via mutagenesis of the substrate binding-specific residues in cyclase homology domain...
February 6, 2018: Applied Biochemistry and Biotechnology
Paula Morales, Israa Isawi, Patricia H Reggio
GPR3, GPR6, and GPR12 are three orphan receptors that belong to the Class A family of G-protein-coupled receptors (GPCRs). These GPCRs share over 60% of sequence similarity among them. Because of their close phylogenetic relationship, GPR3, GPR6, and GPR12 share a high percentage of homology with other lipid receptors such as the lysophospholipid and the cannabinoid receptors. On the basis of sequence similarities at key structural motifs, these orphan receptors have been related to the cannabinoid family. However, further experimental data are required to confirm this association...
February 1, 2018: Drug Metabolism Reviews
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
Xuan Yu, John N Stallone, Cristine L Heaps, Guichun Han
Estrogen exerts protective effects against cardiovascular diseases in premenopausal women, but is associated with an increased risk of both coronary heart disease and stroke in older postmenopausal women. Studies have shown that activation of the G-protein-coupled estrogen receptor 1 (GPER) can cause either relaxation or contraction of arteries. It is highly likely that these dual actions of GPER may contribute to the seemingly paradoxical effects of estrogen in regulating coronary artery function. The objective of this study was to test the hypothesis that activation of GPER enhances agonist-stimulated porcine coronary artery contraction via epidermal growth factor receptor (EGFR) transactivation and its downstream extracellular signal-regulated kinases (ERK1/2) pathway...
2018: PloS One
Adeline Orts-Del'Immagine, Jason R Pugh
Parallel fiber synapses in the cerebellum express a wide range of presynaptic receptors. However, presynaptic receptor expression at individual parallel fiber synapses is quite heterogeneous, suggesting physiological mechanisms regulate presynaptic receptor expression. We investigated changes in presynaptic GABAB receptors at parallel fiber-stellate cell synapses in acute cerebellar slices from juvenile mice. GABAB receptor-mediated inhibition of EPSCs is remarkably diverse at these synapses, with transmitter release at some synapses inhibited by more than 50% and little or no inhibition at others...
January 23, 2018: Synapse
Suifang Mao, Alok S Shah, Thomas O Moninger, Lynda S Ostedgaard, Lin Lu, Xiao Xiao Tang, Ian M Thornell, Leah R Reznikov, Sarah E Ernst, Philip H Karp, Ping Tan, Shaf Keshavjee, Mahmoud H Abou Alaiwa, Michael J Welsh
Differentiated airway epithelia produce sonic hedgehog (SHH), which is found in the thin layer of liquid covering the airway surface. Although previous studies showed that vertebrate HH signaling requires primary cilia, as airway epithelia mature, the cells lose primary cilia and produce hundreds of motile cilia. Thus, whether airway epithelia have apical receptors for SHH has remained unknown. We discovered that motile cilia on airway epithelial cells have HH signaling proteins, including patched and smoothened...
January 22, 2018: Proceedings of the National Academy of Sciences of the United States of America
Appalaraju Jaggupilli, Premnath Dhanaraj, Alexander Pritchard, John L Sorensen, Shyamala Dakshinamurti, Prashen Chelikani
Adenylyl cyclases (ACs) are membrane bound enzymes that catalyze the production of cAMP from ATP in response to the activation by G-protein Gαs. Different isoforms of ACs are ubiquitously expressed in different tissues involved in regulatory mechanisms in response to specific stimulants. There are 9 AC isoforms present in humans, with AC5 and AC6 proposed to play a vital role in cardiac functions. The activity of AC6 is sensitive to nitric oxide, such that nitrosylation of the protein might regulate its function...
January 11, 2018: Molecular and Cellular Biochemistry
Xiaochao Tan, Priyam Banerjee, Xin Liu, Jiang Yu, Don L Gibbons, Ping Wu, Kenneth L Scott, Lixia Diao, Xiaofeng Zheng, Jing Wang, Ali Jalali, Milind Suraokar, Junya Fujimoto, Carmen Behrens, Xiuping Liu, Chang-Gong Liu, Chad J Creighton, Ignacio I Wistuba, Jonathan M Kurie
Epithelial tumor cells undergo epithelial-to-mesenchymal transition (EMT) to gain metastatic activity. Competing endogenous RNAs (ceRNAs) have binding sites for a common set of microRNAs (miRs) and regulate each other's expression by sponging miRs. Here, we address whether ceRNAs govern EMT-driven metastasis. High miR-181b levels were correlated with an improved prognosis in human lung adenocarcinomas, and metastatic tumor cell lines derived from a murine lung adenocarcinoma model in which metastasis is EMT-driven were enriched in miR-181b targets...
January 11, 2018: Journal of Clinical Investigation
Jacqueline E Siljee, Yi Wang, Adelaide A Bernard, Baran A Ersoy, Sumei Zhang, Aaron Marley, Mark Von Zastrow, Jeremy F Reiter, Christian Vaisse
Most monogenic cases of obesity in humans have been linked to mutations in genes encoding members of the leptin-melanocortin pathway. Specifically, mutations in MC4R, the melanocortin-4 receptor gene, account for 3-5% of all severe obesity cases in humans 1-3 . Recently, ADCY3 (adenylyl cyclase 3) gene mutations have been implicated in obesity 4,5 . ADCY3 localizes to the primary cilia of neurons 6 , organelles that function as hubs for select signaling pathways. Mutations that disrupt the functions of primary cilia cause ciliopathies, rare recessive pleiotropic diseases in which obesity is a cardinal manifestation 7 ...
January 8, 2018: Nature Genetics
Rajender K Motiani, Jyoti Tanwar, Desingu Ayyappa Raja, Ayushi Vashisht, Shivangi Khanna, Sachin Sharma, Sonali Srivastava, Sridhar Sivasubbu, Vivek T Natarajan, Rajesh S Gokhale
Endoplasmic reticulum (ER)-plasma membrane (PM) junctions form functionally active microdomains that connect intracellular and extracellular environments. While the key role of these interfaces in maintenance of intracellular Ca2+ levels has been uncovered in recent years, the functional significance of ER-PM junctions in non-excitable cells has remained unclear. Here, we show that the ER calcium sensor protein STIM1 (stromal interaction molecule 1) interacts with the plasma membrane-localized adenylyl cyclase 6 (ADCY6) to govern melanogenesis...
January 8, 2018: EMBO Journal
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