期刊
JOURNAL OF CELL SCIENCE
卷 118, 期 23, 页码 5637-5646出版社
COMPANY OF BIOLOGISTS LTD
DOI: 10.1242/jcs.02675
关键词
mAKAP; ryanodine receptor; calcineurin; hypertrophy; NFATc
类别
资金
- NHLBI NIH HHS [K08 HL04229, R01 HL075398-02, R01 HL075398, R01 HL082705, R01 HL082705-04] Funding Source: Medline
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 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 beta 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.
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