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Integrating cardiac PIP3 and cAMP signaling through a PKA anchoring function of p110γ.
- Source :
-
Molecular cell [Mol Cell] 2011 Apr 08; Vol. 42 (1), pp. 84-95. - Publication Year :
- 2011
-
Abstract
- Adrenergic stimulation of the heart engages cAMP and phosphoinositide second messenger signaling cascades. Cardiac phosphoinositide 3-kinase p110γ participates in these processes by sustaining β-adrenergic receptor internalization through its catalytic function and by controlling phosphodiesterase 3B (PDE3B) activity via an unknown kinase-independent mechanism. We have discovered that p110γ anchors protein kinase A (PKA) through a site in its N-terminal region. Anchored PKA activates PDE3B to enhance cAMP degradation and phosphorylates p110γ to inhibit PIP(3) production. This provides local feedback control of PIP(3) and cAMP signaling events. In congestive heart failure, p110γ is upregulated and escapes PKA-mediated inhibition, contributing to a reduction in β-adrenergic receptor density. Pharmacological inhibition of p110γ normalizes β-adrenergic receptor density and improves contractility in failing hearts.<br /> (Copyright © 2011 Elsevier Inc. All rights reserved.)
- Subjects :
- Amino Acid Sequence
Animals
Base Sequence
Cell Line
Class Ib Phosphatidylinositol 3-Kinase chemistry
Class Ib Phosphatidylinositol 3-Kinase deficiency
Class Ib Phosphatidylinositol 3-Kinase genetics
Cyclic AMP-Dependent Protein Kinase RIIalpha Subunit metabolism
Cyclic Nucleotide Phosphodiesterases, Type 3 metabolism
DNA genetics
Enzyme Activation
Enzyme Inhibitors pharmacology
Heart Failure drug therapy
Heart Failure metabolism
Humans
Mice
Mice, Inbred C57BL
Mice, Knockout
Molecular Sequence Data
Peptide Fragments chemistry
Peptide Fragments genetics
Peptide Fragments metabolism
Phosphoinositide-3 Kinase Inhibitors
Phosphorylation
Protein Interaction Mapping
Quinoxalines pharmacology
Receptors, Adrenergic, beta metabolism
Second Messenger Systems
Sequence Homology, Amino Acid
Thiazolidinediones pharmacology
A Kinase Anchor Proteins metabolism
Class Ib Phosphatidylinositol 3-Kinase metabolism
Cyclic AMP metabolism
Cyclic AMP-Dependent Protein Kinases metabolism
Myocytes, Cardiac metabolism
Phosphatidylinositol Phosphates metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1097-4164
- Volume :
- 42
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Molecular cell
- Publication Type :
- Academic Journal
- Accession number :
- 21474070
- Full Text :
- https://doi.org/10.1016/j.molcel.2011.01.030