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First published online November 23, 2005
doi: 10.1242/10.1242/jcs.02675

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

Genevieve C. Pare^1,*, Andrea L. Bauman^1,*, Molly McHenry¹, Jennifer J. Carlisle Michel¹, Kimberly L. Dodge-Kafka² and Michael S. Kapiloff^1,

¹ Department of Pediatrics, Department of Cell and Developmental Biology, Heart Research Center, Oregon Health and Science University, NRC5 3181 S.W. Sam Jackson Park Road, Portland, OR 97239, USA
² Calhoun Center for Cardiology University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030, USA

Author for correspondence (e-mail: kapiloff{at}ohsu.edu)

Accepted 5 September 2005

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 Aß 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.

Key words: mAKAP, Ryanodine receptor, Calcineurin, Hypertrophy, NFATc

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