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 cAMPdependent protein kinase A-catalyzed phosphorylation of the ryanodine receptor Ca 2+ -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 A␤ ␤ 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 Ca 2+ signals that promote myocyte hypertrophy. Journal of Cell Science 5638 from the nuclear envelope, we showed that mAKAP was required for the induction of myocyte hypertrophy by this cytokine-regulated signaling pathway (Dodge-Kafka et al., 2005). We now report that mAKAP is important for the induction of myocyte hypertrophy by adrenergic receptor signaling. The ␤-adrenergic receptor stimulates adenylate cyclase and increases intracellular cAMP levels and, subsequently, PKA activity. mAKAP-bound PKA can phosphorylate associated RyR2 (Kapiloff, 2002;Marx et al., 2000;Ruehr et al., 2003), potentiating channel activity (Hain et al., 1995;. It is generally understood that RyR2 mediates Ca 2+ -induced Ca 2+ release from the sarcoplasmic reticulum during excitation-contraction coupling (Fill and Copello, 2002). We have found, however, a small pool of RyR2 associated with mAKAP at the nuclear envelope ). mAKAP-associated RyR2 might regulate the release of Ca 2+ from adjacent, peri-nuclear sarcoplasmic reticulum or the release of putative stores within the nuclear envelope (Abrenica and Gilchrist, 2000). We now present evidence that mAKAP is integral to the induction of ␤-adrenergic-stimulated hypertrophy by participating in the CaN-NFATc signaling pathway. We show further that mAKAP is also relevant to ␣-adrenergic signaling. In contrast to the ␤-adrenergic receptor, the ␣-adrenergic receptor activates phospholipase C and phosphatidyl inositol pathways, resulting in increased intracellular Ca 2+ levels and activation of MAP kinases (including MEK5 and ERK5) and CaN (Dorn and Force, 2005;Nicol et al., 2001). Given the ability of mAKAP to anchor ERK5, PKA, RyR2, and, as shown below, CaN, to the nuclear envelope, we propose that the mAKAP scaffold may serve as an integrator for hypertrophic signa...

No abstract

No abstract