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Regulator of G-protein signaling 6 (RGS6) promotes anxiety and depression by attenuating serotonin-mediated activation of the 5-HT(1A) receptor-adenylyl cyclase axis.
Stewart A, Maity B, Wunsch AM, Meng F, Wu Q, Wemmie JA, Fisher RA
(2014) FASEB J 28: 1735-44
MeSH Terms: 8-Hydroxy-2-(di-n-propylamino)tetralin, Adenylyl Cyclases, Animals, Animals, Newborn, Anxiety, Cells, Cultured, Cerebral Cortex, Depression, Female, Fluvoxamine, Hippocampus, Immunoblotting, Immunohistochemistry, Male, Mice, Phosphorylation, Piperazines, Proto-Oncogene Proteins c-akt, Pyridines, RGS Proteins, Receptor, Serotonin, 5-HT1A, Serotonin, Serotonin Antagonists, Serotonin Receptor Agonists, Serotonin Uptake Inhibitors, Signal Transduction
Show Abstract · Added August 7, 2014
Targeting serotonin (5-HT) bioavailability with selective 5-HT reuptake inhibitors (SSRIs) remains the most widely used treatment for mood disorders. However, their limited efficacy, delayed onset of action, and side effects restrict their clinical utility. Endogenous regulator of G-protein signaling (RGS) proteins have been implicated as key inhibitors of 5-HT(1A)Rs, whose activation is believed to underlie the beneficial effects of SSRIs, but the identity of the specific RGS proteins involved remains unknown. We identify RGS6 as the critical negative regulator of 5-HT(1A)R-dependent antidepressant actions. RGS6 is enriched in hippocampal and cortical neurons, 5-HT(1A)R-expressing cells implicated in mood disorders. RGS6(-/-) mice exhibit spontaneous anxiolytic and antidepressant behavior rapidly and completely reversibly by 5-HT(1A)R blockade. Effects of the SSRI fluvoxamine and 5-HT(1A)R agonist 8-OH-DPAT were also potentiated in RGS6(+/-) mice. The phenotype of RGS6(-/-) mice was associated with decreased CREB phosphorylation in the hippocampus and cortex, implicating enhanced Gα(i)-dependent adenylyl cyclase inhibition as a possible causative factor in the behavior observed in RGS6(-/-) animals. Our results demonstrate that by inhibiting serotonergic innervation of the cortical-limbic neuronal circuit, RGS6 exerts powerful anxiogenic and prodepressant actions. These findings indicate that RGS6 inhibition may represent a viable means to treat mood disorders or enhance the efficacy of serotonergic agents.
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26 MeSH Terms
Absence of Ca2+-stimulated adenylyl cyclases leads to reduced synaptic plasticity and impaired experience-dependent fear memory.
Wieczorek L, Majumdar D, Wills TA, Hu L, Winder DG, Webb DJ, Muglia LJ
(2012) Transl Psychiatry 2: e126
MeSH Terms: Adenylyl Cyclases, Animals, Calcium, Crosses, Genetic, Fear, Gene-Environment Interaction, Hippocampus, Long-Term Potentiation, Membrane Glycoproteins, Mental Recall, Mice, Mice, Inbred C57BL, Mice, Knockout, Nerve Tissue Proteins, Neurogenesis, Neuronal Plasticity, Prosencephalon, Synapses
Show Abstract · Added May 19, 2014
Ca(2+)-stimulated adenylyl cyclase (AC) 1 and 8 are two genes that have been shown to play critical roles in fear memory. AC1 and AC8 couple neuronal activity and intracellular Ca(2+) increases to the production of cyclic adenosine monophosphate and are localized synaptically, suggesting that Ca(2+)-stimulated ACs may modulate synaptic plasticity. Here, we first established that Ca(2+)-stimulated ACs modulate protein markers of synaptic activity at baseline and after learning. Primary hippocampal cell cultures showed that AC1/AC8 double-knockout (DKO) mice have reduced SV2, a synaptic vesicle protein, abundance along their dendritic processes, and this reduction can be rescued through lentivirus delivery of AC8 to the DKO cells. Additionally, phospho-synapsin, a protein implicated in the regulation of neurotransmitter release at the synapse, is decreased in vivo 1 h after conditioned fear (CF) training in DKO mice. Importantly, additional experiments showed that long-term potentiation deficits present in DKO mice are rescued by acutely replacing AC8 in the forebrain, further supporting the idea that Ca(2+)-stimulated AC activity is a crucial modulator of synaptic plasticity. Previous studies have demonstrated that memory is continually modulated by gene-environment interactions. The last set of experiments evaluated the effects of knocking out AC1 and AC8 genes on experience-dependent changes in CF memory. We showed that the strength of CF memory in wild-type mice is determined by previous environment, minimal or enriched, whereas memory in DKO mice is unaffected. Thus, overall these results show that AC1 and AC8 modulate markers of synaptic activity and help integrate environmental information to modulate fear memory.
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18 MeSH Terms
Functional selectivity induced by mGlu₄ receptor positive allosteric modulation and concomitant activation of Gq coupled receptors.
Yin S, Zamorano R, Conn PJ, Niswender CM
(2013) Neuropharmacology 66: 122-32
MeSH Terms: Adenylyl Cyclase Inhibitors, Adenylyl Cyclases, Allosteric Regulation, Animals, Benzopyrans, Calcium, Calcium Signaling, Cell Line, Excitatory Amino Acid Agonists, Excitatory Amino Acid Antagonists, GTP-Binding Protein alpha Subunits, Gq-G11, Glutamic Acid, Guinea Pigs, Histamine, Humans, Phosphatidylinositols, Rats, Receptors, Histamine H1, Receptors, Metabotropic Glutamate, Signal Transduction
Show Abstract · Added February 19, 2015
Metabotropic glutamate receptors (mGlus) are a group of Family C Seven Transmembrane Spanning Receptors (7TMRs) that play important roles in modulating signaling transduction, particularly within the central nervous system. mGlu(4) belongs to a subfamily of mGlus that is predominantly coupled to G(i/o) G proteins. We now report that the ubiquitous autacoid and neuromodulator, histamine, induces substantial glutamate-activated calcium mobilization in mGlu(4)-expressing cells, an effect which is observed in the absence of co-expressed chimeric G proteins. This strong induction of calcium signaling downstream of glutamate activation of mGlu(4) depends upon the presence of H(1) histamine receptors. Interestingly, the potentiating effect of histamine activation does not extend to other mGlu(4)-mediated signaling events downstream of G(i/o) G proteins, such as cAMP inhibition, suggesting that the presence of G(q) coupled receptors such as H(1) may bias normal mGlu(4)-mediated G(i/o) signaling events. When the activity induced by small molecule positive allosteric modulators of mGlu(4) is assessed, the potentiated signaling of mGlu(4) is further biased by histamine toward calcium-dependent pathways. These results suggest that G(i/o)-coupled mGlus may induce substantial, and potentially unexpected, calcium-mediated signaling events if stimulation occurs concomitantly with activation of G(q) receptors. Additionally, our results suggest that signaling induced by small molecule positive allosteric modulators may be substantially biased when G(q) receptors are co-activated. This article is part of a Special Issue entitled 'Metabotropic Glutamate Receptors'.
Copyright © 2012 Elsevier Ltd. All rights reserved.
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20 MeSH Terms
GSK3beta mediates renal response to vasopressin by modulating adenylate cyclase activity.
Rao R, Patel S, Hao C, Woodgett J, Harris R
(2010) J Am Soc Nephrol 21: 428-37
MeSH Terms: Adenylyl Cyclases, Animals, Antidiuretic Agents, Aquaporin 2, Cells, Cultured, Colforsin, Cyclic AMP, Deamino Arginine Vasopressin, Female, Glycogen Synthase Kinase 3, Glycogen Synthase Kinase 3 beta, Kidney Concentrating Ability, Kidney Tubules, Collecting, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, RNA, Messenger, Water Deprivation, Water-Electrolyte Balance
Show Abstract · Added August 19, 2013
Glycogen synthase kinase 3beta (GSK3beta), a serine/threonine protein kinase, is a key target of drug discovery in several diseases, including diabetes and Alzheimer disease. Because lithium, a potent inhibitor of GSK3beta, causes nephrogenic diabetes insipidus, GSK3beta may play a crucial role in regulating water homeostasis. We developed renal collecting duct-specific GSK3beta knockout mice to determine whether deletion of GSK3beta affects arginine vasopressin-dependent renal water reabsorption. Although only mildly polyuric under normal conditions, knockout mice exhibited an impaired urinary concentrating ability in response to water deprivation or treatment with a vasopressin analogue. The knockout mice had reduced levels of mRNA, protein, and membrane localization of the vasopressin-responsive water channel aquaporin 2 compared with wild-type mice. The knockout mice also expressed lower levels of pS256-AQP2, a phosphorylated form crucial for membrane trafficking. Levels of cAMP, a major regulator of aquaporin 2 expression and trafficking, were also lower in the knockout mice. Both GSK3beta gene deletion and pharmacologic inhibition of GSK3beta reduced adenylate cyclase activity. In summary, GSK3beta inactivation or deletion reduces aquaporin 2 expression by modulating adenylate cyclase activity and cAMP generation, thereby impairing responses to vasopressin in the renal collecting duct.
1 Communities
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20 MeSH Terms
RACK1 regulates specific functions of Gbetagamma.
Chen S, Dell EJ, Lin F, Sai J, Hamm HE
(2004) J Biol Chem 279: 17861-8
MeSH Terms: Adenylyl Cyclases, Animals, COS Cells, Cell Line, Cell Membrane, Chemotaxis, Cyclic AMP, Cytosol, Dimerization, Dose-Response Relationship, Drug, Enzyme Activation, GTP-Binding Protein beta Subunits, GTP-Binding Protein gamma Subunits, GTP-Binding Proteins, Gene Expression Regulation, Glutathione Transferase, Humans, Hydrolysis, Interleukin-8, Isoenzymes, Lipid Metabolism, MAP Kinase Signaling System, Microscopy, Confocal, Microscopy, Fluorescence, Neoplasm Proteins, Phospholipase C beta, Protein Binding, Protein Transport, Receptors for Activated C Kinase, Receptors, Cell Surface, Signal Transduction, Transfection, Type C Phospholipases
Show Abstract · Added January 20, 2015
We showed previously that Gbetagamma interacts with Receptor for Activated C Kinase 1 (RACK1), a protein that not only binds activated protein kinase C (PKC) but also serves as an adaptor/scaffold for many signaling pathways. Here we report that RACK1 does not interact with Galpha subunits or heterotrimeric G proteins but binds free Gbetagamma subunits released from activated heterotrimeric G proteins following the activation of their cognate receptors in vivo. The association with Gbetagamma promotes the translocation of RACK1 from the cytosol to the membrane. Moreover, binding of RACK1 to Gbetagamma results in inhibition of Gbetagamma-mediated activation of phospholipase C beta2 and adenylyl cyclase II. However, RACK1 has no effect on other functions of Gbetagamma, such as activation of the mitogen-activated protein kinase signaling pathway or chemotaxis of HEK293 cells via the chemokine receptor CXCR2. Similarly, RACK1 does not affect signal transduction through the Galpha subunits of G(i), G(s), or G(q). Collectively, these findings suggest a role of RACK1 in regulating specific functions of Gbetagamma.
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33 MeSH Terms
Androgen receptor activity at the prostate specific antigen locus: steroidal and non-steroidal mechanisms.
Jia L, Kim J, Shen H, Clark PE, Tilley WD, Coetzee GA
(2003) Mol Cancer Res 1: 385-92
MeSH Terms: Acetylation, Adenylyl Cyclases, Cell Division, Colforsin, Dihydrotestosterone, Genes, Reporter, Histones, Humans, Interleukin-6, Ligands, Luciferases, Male, Promoter Regions, Genetic, Prostate-Specific Antigen, Prostatic Neoplasms, Receptors, Androgen, Tumor Cells, Cultured
Show Abstract · Added May 27, 2014
Ligand-activated androgen receptors (ARs) occupy target genes and recruit histone modifiers that influence transcriptional competency. In LNCaP prostate cancer cells, the natural ligand 5alpha-dihydrotestosterone (DHT) activates transiently transfected AR-responsive promoter constructs; concurrent treatment with the protein kinase A activator forskolin enhanced AR stimulation induced by DHT. Additional treatment with the cytokine IL-6, purportedly an AR activator, markedly inhibited receptor activity. To assess AR activity on natural chromatin-integrated promoters/enhancers, we determined AR occupancy of the endogenous prostate specific antigen (PSA) promoter/enhancer as well as PSA expression in LNCaP cells treated with DHT; AR occupancy of the PSA enhancer was rapid (within 1 h of stimulation), robust (10-fold over background), and sustained (8-16 h). In contrast, AR occupancy of the PSA promoter was only increased by 2-fold. Histone H3 acetylation at both the enhancer and promoter was evident 1-2 h after DHT treatment. Detectable pre- and mature PSA mRNA levels appeared after 1 and 6 h treatment, respectively. Substantial qualitative and quantitative differences in PSA expression and AR occupancy of the PSA enhancer were observed when DHT-induced and ligand-independent activations of the AR were compared; forskolin stimulated PSA mRNA and protein expression, whereas IL-6 inhibited both DHT- and forskolin-stimulated expression. IL-6 did not diminish DHT-dependent AR occupancy of the PSA enhancer but inhibited CBP/p300 recruitment, histone H3 acetylation, and cell proliferation. These findings provide a contextual framework for interpreting the contribution of non-steroidal activation of the AR to signaling in vivo, and have implications for prostate cancer cell growth.
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17 MeSH Terms
Prostaglandin receptor EP2 mediates PGE2 stimulated hypercalcemia in mice in vivo.
Li X, Tomita M, Pilbeam CC, Breyer RM, Raisz LG
(2002) Prostaglandins Other Lipid Mediat 67: 173-80
MeSH Terms: Actins, Adenylyl Cyclases, Animals, Blotting, Northern, Bone and Bones, Calcium, Carrier Proteins, Cyclic AMP, Dinoprostone, Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating), Glycoproteins, Hypercalcemia, Male, Membrane Glycoproteins, Mice, Mice, Inbred C57BL, Mice, Knockout, Osteoblasts, Osteoclasts, Osteogenesis, Osteoprotegerin, RANK Ligand, RNA, Messenger, Receptor Activator of Nuclear Factor-kappa B, Receptors, Cytoplasmic and Nuclear, Receptors, Prostaglandin E, Receptors, Prostaglandin E, EP2 Subtype, Receptors, Tumor Necrosis Factor
Show Abstract · Added December 21, 2013
Prostaglandin E2 (PGE2) can stimulate bone resorption by a cyclic AMP-dependent pathway. Two PGE2 receptors, EP2 and EP4 have been shown to play a role in PGE2 stimulation of osteoclast formation. In primary osteoblastic cell cultures from EP2 wild type (EP2 +/+) mice, PGE2 (0.1 microM) increased cyclic AMP production 3.5-fold, but PGE2 had no effect on cells from mice in which the EP2 receptor had been deleted (EP2 -/-). To examine the role of the EP2 receptor in the resorption response in vivo we injected PGE2 in EP2 -/- mice, and compared them with EP2 +/+ mice. Injection of PGE2 (3 mg/kg, four times daily for three days) in 9- to 12-month-old male mice on a 129 SvEv background increased serum calcium from 9.8 +/- 0.5 to 10.7 +/- 0.3 mg/dl (P < 0.01) in EP2 +/+ mice but not in EP2 -/- mice (10.1 +/- 0.3 vs. 10.2 +/- 0.3 mg/dl). PGE2 injection (6 mg/kg twice a day for three days) in 3-4 month old male mice on a C57 BL/6 X 129 SvEv background increased calcium from 8.2 +/- 0.1 to 9.0 +/- 0.3 mg/dl (P < 0.05) in EP2 +/+ mice but had no effect in EP2-/- mice (8.4 +/- 0.1 vs. 8.3 +/- 0.2 mg/dl). Injection of PGE2 over the calvariae of EP2 +/+ and EP2-/- mice increased the expression of receptor activator of nuclear factor kappaB ligand (RANKL) both locally and in the tibia, but RANKL responses were lower in EP2 -/- mice. We conclude that EP2 receptor plays a role in the hypercalcemic response to PGE2. This impaired response in EP2 -/- mice may be due to decreased ability to stimulate cyclic AMP and in part, to a smaller increase in the expression of RANKL mRNA.
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28 MeSH Terms
Mapping the lethal factor and edema factor binding sites on oligomeric anthrax protective antigen.
Cunningham K, Lacy DB, Mogridge J, Collier RJ
(2002) Proc Natl Acad Sci U S A 99: 7049-53
MeSH Terms: Adenylyl Cyclases, Animals, Antigens, Bacterial, Bacillus anthracis, Bacterial Toxins, Binding Sites, CHO Cells, Chromosome Mapping, Cricetinae, Dimerization, Ligands, Models, Molecular, Mutagenesis, Protein Structure, Tertiary
Show Abstract · Added May 7, 2013
Assembly of anthrax toxin complexes at the mammalian cell surface involves competitive binding of the edema factor (EF) and lethal factor (LF) to heptameric oligomers and lower order intermediates of PA(63), the activated carboxyl-terminal 63-kDa fragment of protective antigen (PA). We used sequence differences between PA(63) and homologous PA-like proteins to delineate a region within domain 1' of PA that may represent the binding site for these ligands. Substitution of alanine for any of seven residues in or near this region (R178, K197, R200, P205, I207, I210, and K214) strongly inhibited ligand binding. Selected mutations from this set were introduced into two oligomerization-deficient PA mutants, and the mutants were used in various combinations to map the single ligand site within dimeric PA(63). The site was found to span the interface between two adjacent subunits, explaining the dependence of ligand binding on PA oligomerization. The locations of residues comprising the site suggest that a single ligand molecule sterically occludes two adjacent sites, consistent with the finding that the PA(63) heptamer binds a maximum of three ligand molecules. These results elucidate the process by which the components of anthrax toxin, and perhaps other binary bacterial toxins, assemble into toxic complexes.
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14 MeSH Terms
The lethal and edema factors of anthrax toxin bind only to oligomeric forms of the protective antigen.
Mogridge J, Cunningham K, Lacy DB, Mourez M, Collier RJ
(2002) Proc Natl Acad Sci U S A 99: 7045-8
MeSH Terms: Adenylyl Cyclases, Antigens, Bacterial, Bacillus anthracis, Bacterial Toxins, Ligands, Mutagenesis, Oligopeptides, Solutions
Show Abstract · Added May 7, 2013
The three proteins that comprise anthrax toxin, edema factor (EF), lethal factor (LF), and protective antigen (PA), assemble at the mammalian cell surface into toxic complexes. After binding to its receptor, PA is proteolytically activated, yielding a carboxyl-terminal 63-kDa fragment (PA(63)) that coordinates assembly of the complexes, promotes their endocytosis, and translocates EF and LF to the cytosol. PA(63) spontaneously oligomerizes to form symmetric ring-shaped heptamers that are capable of binding three molecules of EF and/or LF as competing ligands. To determine whether binding of these ligands depends on oligomerization of PA(63), we prepared two oligomerization-deficient forms of this protein, each mutated on a different PA(63)-PA(63) contact face. In solution or when bound to receptors on Chinese hamster ovary K1 cells, neither mutant alone bound ligand, but a mixture of them did. After the two mutants were proteolytically activated and mixed with ligand in solution, a ternary complex was isolated containing one molecule of each protein. Thus EF and LF bind stably only to PA(63) dimers or higher order oligomers. These findings are relevant to the kinetics and pathways of assembly of anthrax toxin complexes.
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8 MeSH Terms
Differential expression of adenosine receptors in human endothelial cells: role of A2B receptors in angiogenic factor regulation.
Feoktistov I, Goldstein AE, Ryzhov S, Zeng D, Belardinelli L, Voyno-Yasenetskaya T, Biaggioni I
(2002) Circ Res 90: 531-8
MeSH Terms: Adenylyl Cyclases, Angiogenesis Inducing Agents, Animals, CHO Cells, Cricetinae, Endothelial Growth Factors, Endothelium, Vascular, Genes, Reporter, Heterotrimeric GTP-Binding Proteins, Humans, Inositol Phosphates, Interleukin-8, Luciferases, Lymphokines, Microcirculation, Neovascularization, Physiologic, Promoter Regions, Genetic, Purinergic P1 Receptor Agonists, RNA, Messenger, Receptor, Adenosine A2A, Receptor, Adenosine A2B, Receptors, Purinergic P1, Second Messenger Systems, Transfection, Vascular Endothelial Growth Factor A, Vascular Endothelial Growth Factors, Veins
Show Abstract · Added December 10, 2013
Adenosine has been reported to stimulate or inhibit the release of angiogenic factors depending on the cell type examined. To test the hypothesis that differential expression of adenosine receptor subtypes contributes to endothelial cell heterogeneity, we studied microvascular (HMEC-1) and umbilical vein (HUVEC) human endothelial cells. Based on mRNA level and stimulation of adenylate cyclase, we found that HUVECs preferentially express A2A adenosine receptors and HMEC-1 preferentially express A2B receptors. Neither cells expressed A1 or A3 receptors. The nonselective adenosine agonist 5'-N-ethylcarboxamidoadenosine (NECA) increased expression of interleukin-8 (IL-8), basic fibroblast growth factor (bFGF), and vascular endothelial growth factor (VEGF) in HMEC-1, but had no effect in HUVECs. In contrast, the selective A2A agonist 2-p-(2-carboxyethyl)phenylethylamino-NECA (CGS 21680) had no effect on expression of these angiogenic factors. Cotransfection of each type of adenosine receptors with a luciferase reporter in HMEC-1 showed that A2B receptors, but not A1, A2A, or A3, activated IL-8 and VEGF promoters. These effects were mimicked by constitutively active alphaG(q), alphaG12, and alphaG13, but not alphaG(s) or alphaG(i1-3). Furthermore, stimulation of phospholipase C indicated coupling of A2B receptors to G(q) proteins in HMEC-1. Thus, differential expression of adenosine receptor subtypes contributes to functional heterogeneity of human endothelial cells. A2B receptors, predominantly expressed in human microvascular cells, modulate expression of angiogenic factors via coupling to G(q), and possibly via G12/13.
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27 MeSH Terms