Linked Life Data

17038640

Source:http://linkedlifedata.com/resource/pubmed/id/17038640

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PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
10
pubmed:dateCreated
2006-11-10
pubmed:abstractText
Beta(1)- and beta(2)-adrenergic receptors (betaARs) are known to differentially regulate cardiomyocyte contraction and growth. We tested the hypothesis that these differences are attributable to spatial compartmentation of the second messenger cAMP. Using a fluorescent resonance energy transfer (FRET)-based approach, we directly monitored the spatial and temporal distribution of cAMP in adult cardiomyocytes. We developed a new cAMP-FRET sensor (termed HCN2-camps) based on a single cAMP binding domain of the hyperpolarization activated cyclic nucleotide-gated potassium channel 2 (HCN2). Its cytosolic distribution, high dynamic range, and sensitivity make HCN2-camps particularly well suited to monitor subcellular localization of cardiomyocyte cAMP. We generated HCN2-camps transgenic mice and performed single-cell FRET imaging on freshly isolated cardiomyocytes. Whole-cell superfusion with isoproterenol showed a moderate elevation of cAMP. Application of various phosphodiesterase (PDE) inhibitors revealed stringent control of cAMP through PDE4>PDE2>PDE3. The beta(1)AR-mediated cAMP signals were entirely dependent on PDE4 activity, whereas beta(2)AR-mediated cAMP was under control of multiple PDE isoforms. beta(1)AR subtype-specific stimulation yielded approximately 2-fold greater cAMP responses compared with selective beta(2)-subtype stimulation, even on treatment with the nonselective PDE inhibitor 3-isobutyl-1-methylxanthine (IBMX) (DeltaFRET, 17.3+/-1.3% [beta(1)AR] versus 8.8+/-0.4% [beta(2)AR]). Treatment with pertussis toxin to inactivate G(i) did not affect cAMP production. Localized beta(1)AR stimulation generated a cAMP gradient propagating throughout the cell, whereas local beta(2)AR stimulation did not elicit marked cAMP diffusion. Our data reveal that in adult cardiac myocytes, beta(1)ARs induce far-reaching cAMP signals, whereas beta(2)AR-induced cAMP remains locally confined.
pubmed:commentsCorrections
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Nov
pubmed:issn
1524-4571
pubmed:author
pubmed:issnType
Electronic
pubmed:day
10
pubmed:volume
99
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
1084-91
pubmed:meshHeading
pubmed-meshheading:17038640-Adrenergic beta-Agonists, pubmed-meshheading:17038640-Animals, pubmed-meshheading:17038640-Biosensing Techniques, pubmed-meshheading:17038640-Cyclic AMP, pubmed-meshheading:17038640-Fluorescence Resonance Energy Transfer, pubmed-meshheading:17038640-Humans, pubmed-meshheading:17038640-Ion Channels, pubmed-meshheading:17038640-Isoenzymes, pubmed-meshheading:17038640-Mice, pubmed-meshheading:17038640-Mice, Transgenic, pubmed-meshheading:17038640-Models, Molecular, pubmed-meshheading:17038640-Myocytes, Cardiac, pubmed-meshheading:17038640-Phosphoric Diester Hydrolases, pubmed-meshheading:17038640-Protein Structure, Tertiary, pubmed-meshheading:17038640-Receptors, Adrenergic, beta-1, pubmed-meshheading:17038640-Receptors, Adrenergic, beta-2, pubmed-meshheading:17038640-Signal Transduction
pubmed:year
2006
pubmed:articleTitle
Cyclic AMP imaging in adult cardiac myocytes reveals far-reaching beta1-adrenergic but locally confined beta2-adrenergic receptor-mediated signaling.
pubmed:affiliation
Institute of Pharmacology and Toxicology, University of Wuerzburg, Germany.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't