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3. Cannabidiol displays unexpectedly high potency as an antagonist of CB1 and CB2 receptor agonists in vitro

Author

Thomas, A, Baillie, G L, Phillips, A M, Razdan, R K, Ross, R A, and Pertwee, R G

Subjects
Morpholines, Anti-Inflammatory Agents, CHO Cells, In Vitro Techniques, Naphthalenes, Transfection, Receptor, Cannabinoid, CB2, Mice, Cricetulus, Phenols, Piperidines, Receptor, Cannabinoid, CB1, Cyclohexanes, Cricetinae, Animals, Cannabidiol, Humans, Receptors, Cannabinoid, Cannabinoid Receptor Antagonists, Cannabinoid Receptor Agonists, Mice, Knockout, Camphanes, Dose-Response Relationship, Drug, Cell Membrane, Brain, Cyclohexanols, Research Papers, Benzoxazines, Mice, Inbred C57BL, Guanosine 5'-O-(3-Thiotriphosphate), Pyrazoles, Rimonabant, Protein Binding
Abstract

A nonpsychoactive constituent of the cannabis plant, cannabidiol has been demonstrated to have low affinity for both cannabinoid CB1 and CB2 receptors. We have shown previously that cannabidiol can enhance electrically evoked contractions of the mouse vas deferens, suggestive of inverse agonism. We have also shown that cannabidiol can antagonize cannabinoid receptor agonists in this tissue with a greater potency than we would expect from its poor affinity for cannabinoid receptors. This study aimed to investigate whether these properties of cannabidiol extend to CB1 receptors expressed in mouse brain and to human CB2 receptors that have been transfected into CHO cells.The [35S]GTPS binding assay was used to determine both the efficacy of cannabidiol and the ability of cannabidiol to antagonize cannabinoid receptor agonists (CP55940 and R-(+)-WIN55212) at the mouse CB1 and the human CB2 receptor.This paper reports firstly that cannabidiol displays inverse agonism at the human CB2 receptor. Secondly, we demonstrate that cannabidiol is a high potency antagonist of cannabinoid receptor agonists in mouse brain and in membranes from CHO cells transfected with human CB2 receptors.This study has provided the first evidence that cannabidiol can display CB2 receptor inverse agonism, an action that appears to be responsible for its antagonism of CP55940 at the human CB2 receptor. The ability of cannabidiol to behave as a CB2 receptor inverse agonist may contribute to its documented anti-inflammatory properties.

Published
2007

4. The role of the PDE4D cAMP phosphodiesterase in the regulation of glucagon-like peptide-1 release.

Author

Ong, W. K., Gribble, F. M., Reimann, F., Lynch, M. J., Houslay, M. D., Baillie, G. S., Furman, B. L., and Pyne, N. J.

Subjects
PHOSPHODIESTERASES, PHOSPHATASES, CYCLIC nucleotide phosphodiesterases, CELL lines, GLUCOSE, ANIMALS, CYCLIC adenylic acid, EPITHELIAL cells, ESTERASES, HETEROCYCLIC compounds, ISOENZYMES, ISOQUINOLINE, MICE, RATS, SULFONAMIDES, GLUCAGON-like peptide 1, PHOSPHODIESTERASE inhibitors, PROTEIN kinase inhibitors, CHEMICAL inhibitors, PHARMACODYNAMICS
Abstract

Background and Purpose: Increases in intracellular cyclic AMP (cAMP) augment the release/secretion of glucagon-like peptide-1 (GLP-1). As cAMP is hydrolysed by cAMP phosphodiesterases (PDEs), we determined the role of PDEs and particularly PDE4 in regulating GLP-1 release.Experimental Approach: GLP-1 release, PDE expression and activity were investigated using rats and GLUTag cells, a GLP-1-releasing cell line. The effects of rolipram, a selective PDE4 inhibitor both in vivo and in vitro and stably overexpressed catalytically inactive PDE4D5 (D556A-PDE4D5) mutant in vitro on GLP-1 release were investigated.Key Results: Rolipram (1.5 mg x kg(-1) i.v.) increased plasma GLP-1 concentrations approximately twofold above controls in anaesthetized rats and enhanced glucose-induced GLP-1 release in GLUTag cells (EC(50) approximately 1.2 nmol x L(-1)). PDE4D mRNA transcript and protein were detected in GLUTag cells using RT-PCR with gene-specific primers and Western blotting with a specific PDE4D antibody respectively. Moreover, significant PDE activity was inhibited by rolipram in GLUTag cells. A GLUTag cell clone (C1) stably overexpressing the D556A-PDE4D5 mutant, exhibited elevated intracellular cAMP levels and increased basal and glucose-induced GLP-1 release compared with vector-transfected control cells. A role for intracellular cAMP/PKA in enhancing GLP-1 release in response to overexpression of D556A-PDE4D5 mutant was demonstrated by the finding that the PKA inhibitor H89 reduced both basal and glucose-induced GLP-1 release by 37% and 39%, respectively, from C1 GLUTag cells.Conclusions and Implications: PDE4D may play an important role in regulating intracellular cAMP linked to the regulation of GLP-1 release. [ABSTRACT FROM AUTHOR]

Published
2009
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5. Integrating Cardiac PIP3 and cAMP Signaling through a PKA Anchoring Function of p110γ

Author

Guido Iaccarino, Lorene K. Langeberg, Allan J. Dunlop, Reinhard Wetzker, Gitte Neubauer, Alessia Perino, Fulvio Morello, Giuseppe Lembo, Gaetano Santulli, Federico Damilano, Renzo Levi, Fiorella Altruda, George S. Baillie, Enrico Ferrero, Lorenzo Silengo, John D. Scott, Catherine T Pawson, Romy Walser, Emilio Hirsch, Stephane Heymans, Alessandra Ghigo, Miles D. Houslay, Matthias P. Wymann, Perino, A., Ghigo, A., Ferrero, E., Morello, F., Santulli, G., Baillie, G., Damilano, F., Dunlop, A., Pawson, C., Walser, R., Levi, R., Altruda, F., Silengo, L., Langeberg, L., Neubauer, G., Heymans, S., Lembo, G., Wymann, M., Wetzker, R., Houslay, M., Iaccarino, G., Scott, J., Hirsch, E., Cardiologie, and RS: CARIM School for Cardiovascular Diseases

Subjects
drug therapy/metabolism, A Kinase Anchor Proteins, Sequence Homology, heart failure, 030204 cardiovascular system & hematology, Inbred C57BL, Second Messenger Systems, Mice, 0302 clinical medicine, Phosphatidylinositol Phosphates, Cyclic AMP-Dependent Protein Kinase RIIalpha Subunit, Protein Interaction Mapping, Receptors, Cyclic AMP, Class Ib Phosphatidylinositol 3-Kinase, Myocytes, Cardiac, genetics, Enzyme Inhibitors, Phosphorylation, pi3k, Receptor, Phosphoinositide-3 Kinase Inhibitors, Mice, Knockout, 0303 health sciences, Cell biology, Amino Acid, Adrenergic, Second messenger system, pka, Type 3, Cardiac, Cyclic Nucleotide Phosphodiesterases, medicine.medical_specialty, Knockout, Molecular Sequence Data, Biology, metabolism, Amino Acid Sequence, Animals, Base Sequence, Cell Line, antagonists /&/ inhibitors/chemistry/deficiency/genetics/metabolism, Cyclic AMP-Dependent Protein Kinases, DNA, Enzyme Activation, pharmacology, Heart Failure, Humans, Myocytes, Peptide Fragments, chemistry/genetics/metabolism, Quinoxalines, beta, Thiazolidinediones, Article, Contractility, 03 medical and health sciences, Enzyme activator, Downregulation and upregulation, Internal medicine, Receptors, Adrenergic, beta, medicine, Protein kinase A, Molecular Biology, 030304 developmental biology, Sequence Homology, Amino Acid, Cell Biology, Cyclic Nucleotide Phosphodiesterases, Type 3, heart failure cAMP PKA PI3K signal transduction, Mice, Inbred C57BL, Endocrinology
Abstract

Adrenergic stimulation of the heart engages cAMP and phosphoinositide second messenger signaling cascades. Cardiac phosphoinositide 3-kinase p110 gamma participates in these processes by sustaining beta-adrenergic receptor internalization through its catalytic function and by controlling phosphodiesterase 3B (PDE3B) activity via an unknown kinase-independent mechanism. We have discovered that p110 gamma anchors protein kinase A (PKA) through a site in its N-terminal region. Anchored PKA activates PDE3B to enhance cAMP degradation and phosphorylates p110 gamma to inhibit PIP3 production. This provides local feedback control of PIP3 and cAMP signaling events. In congestive heart failure, p110 gamma is upregulated and escapes PKA-mediated inhibition, contributing to a reduction in beta-adrenergic receptor density. Pharmacological inhibition of p110 gamma normalizes beta-adrenergic receptor density and improves contractility in failing hearts.

Published
2011

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