Abstract
Protein kinase A (PKA) is a key regulatory enzyme that, on activation by cAMP, modulates a wide variety of cellular functions. PKA isoforms type I and type II possess different structural features and biochemical characteristics, resulting in nonredundant function. However, how different PKA isoforms expressed in the same cell manage to perform distinct functions on activation by the same soluble intracellular messenger, cAMP, remains to be established. Here, we provide a mechanism for the different function of PKA isoforms subsets in cardiac myocytes and demonstrate that PKA-RI and PKA-RII, by binding to AKAPs (A kinase anchoring proteins), are tethered to different subcellular locales, thus defining distinct intracellular signaling compartments. Within such compartments, PKA-RI and PKA-RII respond to distinct, spatially restricted cAMP signals generated in response to specific G protein-coupled receptor agonists and regulated by unique subsets of the cAMP degrading phosphodiesterases. The selective activation of individual PKA isoforms thus leads to phosphorylation of unique subsets of downstream targets.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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A Kinase Anchor Proteins / metabolism
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Animals
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Animals, Newborn
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Biosensing Techniques
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CHO Cells
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Calcium-Binding Proteins / metabolism
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Cricetinae
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Cricetulus
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Cyclic AMP / metabolism*
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Cyclic AMP-Dependent Protein Kinase Type I / genetics
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Cyclic AMP-Dependent Protein Kinase Type I / metabolism*
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Cyclic AMP-Dependent Protein Kinase Type II / genetics
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Cyclic AMP-Dependent Protein Kinase Type II / metabolism*
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Fluorescence Recovery After Photobleaching
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Fluorescence Resonance Energy Transfer
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GTP-Binding Protein alpha Subunits, Gi-Go / metabolism
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Guanine Nucleotide Exchange Factors / metabolism
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Myocytes, Cardiac / drug effects
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Myocytes, Cardiac / enzymology*
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Phosphoric Diester Hydrolases / metabolism
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Phosphorylation
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Rats
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Rats, Sprague-Dawley
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Receptors, G-Protein-Coupled / agonists
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Receptors, G-Protein-Coupled / metabolism
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Recombinant Fusion Proteins / metabolism
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Signal Transduction* / drug effects
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Time Factors
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Transfection
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Troponin I / metabolism
Substances
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A Kinase Anchor Proteins
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Calcium-Binding Proteins
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Guanine Nucleotide Exchange Factors
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Receptors, G-Protein-Coupled
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Recombinant Fusion Proteins
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Troponin I
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phospholamban
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Cyclic AMP
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Cyclic AMP-Dependent Protein Kinase Type I
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Cyclic AMP-Dependent Protein Kinase Type II
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Phosphoric Diester Hydrolases
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GTP-Binding Protein alpha Subunits, Gi-Go