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Integrating Cardiac PIP3 and cAMP Signaling through a PKA Anchoring Function of p110γ
- Source :
- Molecular Cell, 42(1), 84-95. Cell Press
- Publication Year :
- 2011
-
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.
- 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
Subjects
Details
- Language :
- English
- ISSN :
- 10972765
- Database :
- OpenAIRE
- Journal :
- Molecular Cell, 42(1), 84-95. Cell Press
- Accession number :
- edsair.doi.dedup.....d7601f3d51b294fe8d38e43cecb82a6f