An adenylyl cyclase-mAKAP β signaling complex regulates cAMP levels in cardiac myocytes

Michael S. Kapiloff, Leslie A. Piggott, Rachna Sadana, Jinliang Li, Lorena A. Heredia, Edward Henson, Riad Efendiev, Carmen W. Dessauer

Research output: Contribution to journalArticle

73 Scopus citations

Abstract

Protein kinase A-anchoring proteins (AKAPs) play important roles in the compartmentation of cAMP signaling, anchoring protein kinase A (PKA) to specific cellular organelles and serving as scaffolds that assemble localized signaling cascades. Although AKAPs have been recently shown to bind adenylyl cyclase (AC), the functional significance of this association has not been studied. In cardiac myocytes, the muscle protein kinase A-anchoring protein β (mAKAPβ) coordinates cAMP-dependent, calcium, and MAP kinase pathways and is important for cellular hypertrophy. We now show that mAKAPβ selectively binds type 5 AC in the heart and that mAKAPβ-associated AC activity is absent in AC5 knock-out hearts. Consistent with its known inhibition by PKA phosphorylation, AC5 is inhibited by association with mAKAPβ-PKA complexes. AC5 binds to a unique N-terminal site on mAKAP-(245-340), and expression of this peptide disrupts endogenous mAKAPβ-AC association. Accordingly, disruption of mAKAPβa-AC5 complexes in neonatal cardiac myocytes results in increased cAMP and hypertrophy in the absence of agonist stimulation. Taken together, these results show that the association of AC5 with the mAKAPβ complex is required for the regulation of cAMP second messenger controlling cardiac myocyte hypertrophy.

Original languageEnglish (US)
Pages (from-to)23540-23546
Number of pages7
JournalJournal of Biological Chemistry
Volume284
Issue number35
DOIs
StatePublished - Aug 28 2009

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Kapiloff, M. S., Piggott, L. A., Sadana, R., Li, J., Heredia, L. A., Henson, E., Efendiev, R., & Dessauer, C. W. (2009). An adenylyl cyclase-mAKAP β signaling complex regulates cAMP levels in cardiac myocytes. Journal of Biological Chemistry, 284(35), 23540-23546. https://doi.org/10.1074/jbc.M109.030072