Phosphodiesterase 4D is required for β2 adrenoceptor subtype-specific signaling in cardiac myocytes

Yang Kevin Xiang, Fabio Naro, Maria Zoudilova, S. L Catherine Jin, Marco Conti, Brian Kobilka

Research output: Contribution to journalArticlepeer-review

95 Scopus citations

Abstract

β adrenoceptor (βAR) signaling is finely regulated to mediate the sympathetic nervous system control of cardiovascular function. In neonatal cardiac myocytes, β1AR activates the conventional G s/cAMP pathway, whereas β2AR sequentially activates both the Gs and Gi pathways to regulate the myocyte contraction rate. Here, we show that phosphodiesterase 4D (PDE4D) selectively impacts signaling by β2AR in neonatal cardiac myocytes, while having little or no effect on β1AR signaling. Although β2AR activation leads to an increase in cAMP production, the cAMP generated does not have access to the protein kinase A-dependent signaling pathways by which the β1AR regulates the contraction rate. However, this restricted access is lost in the presence of PDE4 inhibitors or after ablation of PDE4D. These results not only suggest that PDE4D is an integral component of the β2AR signaling complex, but also underscore the critical role of subcellular cAMP regulation in the complex control of receptor signaling. They also illustrate a mechanism for fine-tuned βAR subtype signaling specificity and intensity in the cardiac system.

Original languageEnglish (US)
Pages (from-to)909-914
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume102
Issue number3
DOIs
StatePublished - Jan 18 2005
Externally publishedYes

Keywords

  • Camp
  • Heart
  • Knockout

ASJC Scopus subject areas

  • Genetics
  • General

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