The mAKAP complex participates in the induction of cardiac myocyte hypertrophy by adrenergic receptor signaling

Genevieve C. Pare, Andrea L. Bauman, Molly McHenry, Jennifer J. Carlisle Michel, Kimberly L. Dodge-Kafka, Michael S. Kapiloff

Research output: Contribution to journalArticlepeer-review

92 Scopus citations

Abstract

Maladaptive cardiac hypertrophy can progress to congestive heart failure, a leading cause of morbidity and mortality in the United States. A better understanding of the intracellular signal transduction network that controls myocyte cell growth may suggest new therapeutic directions. mAKAP is a scaffold protein that has recently been shown to coordinate signal transduction enzymes important for cytokine-induced cardiac hypertrophy. We now extend this observation and show mAKAP is important for adrenergic-mediated hypertrophy. One function of the mAKAP complex is to facilitate cAMP-dependent protein kinase A-catalyzed phosphorylation of the ryanodine receptor Ca2+-release channel. Experiments utilizing inhibition of the ryanodine receptor, RNA interference of mAKAP expression and replacement of endogenous mAKAP with a mutant form that does not bind to protein kinase A demonstrate that the mAKAP complex contributes to pro-hypertrophic signaling. Further, we show that calcineurin AP associates with mAKAP and that the formation of the mAKAP complex is required for the full activation of the pro-hypertrophic transcription factor NFATc. These data reveal a novel function of the mAKAP complex involving the integration of cAMP and Ca2+ signals that promote myocyte hypertrophy.

Original languageEnglish (US)
Pages (from-to)5637-5646
Number of pages10
JournalJournal of Cell Science
Volume118
Issue number23
DOIs
StatePublished - Dec 1 2005

Keywords

  • Calcineurin
  • Hypertrophy
  • mAKAP
  • NFATc
  • Ryanodine receptor

ASJC Scopus subject areas

  • Cell Biology

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