RGD Reference Report - Differential association of phosphodiesterase 4D isoforms with beta2-adrenoceptor in cardiac myocytes. - Rat Genome Database

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Differential association of phosphodiesterase 4D isoforms with beta2-adrenoceptor in cardiac myocytes.

Authors: De Arcangelis, V  Liu, R  Soto, D  Xiang, Y 
Citation: De Arcangelis V, etal., J Biol Chem. 2009 Dec 4;284(49):33824-32. doi: 10.1074/jbc.M109.020388. Epub 2009 Oct 1.
RGD ID: 7327160
Pubmed: PMID:19801680   (View Abstract at PubMed)
PMCID: PMC2797152   (View Article at PubMed Central)
DOI: DOI:10.1074/jbc.M109.020388   (Journal Full-text)

cAMP and protein kinase A (PKA) activation represents a key signaling mechanism upon beta-adrenergic stimulation under stress. Both beta(1)- and beta(2)-adrenoreceptor (ARs) subtypes induce cAMP accumulation, yet play distinct roles in cardiac contraction and myocyte apoptosis. Differences in controlling cAMP/PKA activities through the assembly of complexes between the receptors and cAMP-specific phosphodiesterases contribute to the distinct biological outcomes. Here, we demonstrate that beta(2)ARs form signaling complexes with a set of PDE4D isoforms expressed in cardiac myocytes. PDE4D9 and PDE4D8 bind to the beta(2)AR at resting conditions; however, agonist stimulation induces dissociation of PDE4D9 from the receptor but recruitment of PDE4D8 to the receptor. Agonist stimulation also induces recruitment of PDE4D5 to the beta(2)AR. Moreover, the receptor-associated PDE4D isoforms play distinct roles in controlling cAMP activities and regulating the PKA phosphorylation of the receptor and myocyte contraction rate responses. Knockdown of PDE4D9 with short hairpin RNA enhances the beta(2)AR-induced cAMP signaling, whereas knockdown of PDE4D8 only slightly prolongs the receptor-induced cAMP signaling in myocytes. Inhibition of PDE4D9 and PDE4D5 enhances the base-line levels of contraction rates, whereas inhibition of PDE4D9 and PDE4D8 enhances the maximal contraction rate increases upon activation of beta(2)AR. Our data underscore the complex regulation of intracellular cAMP by beta(2)AR-associated phosphodiesterase enzymes to enforce the specificity of the receptor signaling for physiological responses.

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process

Molecular Function
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
beta-2 adrenergic receptor binding enablesIPIUniProtKB:P187627327160PMID:19801680BHF-UCL 
signaling receptor regulator activity enablesIMP 7327160PMID:19801680BHF-UCL 

Objects Annotated

Genes (Rattus norvegicus)
Pde4d  (phosphodiesterase 4D)

Additional Information