The mAKAP complex participates in the induction of cardiac myocyte hypertrophy by adrenergic receptor signaling.
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 Abeta 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.
Pare
Genevieve C
GC
Department of Pediatrics, Heart Research Center, Oregon Health and Science University, NRC5 3181 S.W. Sam Jackson Park Road, Portland, OR 97239, USA.
Bauman
Andrea L
AL
McHenry
Molly
M
Michel
Jennifer J Carlisle
JJ
Dodge-Kafka
Kimberly L
KL
Kapiloff
Michael S
MS
D054758:A Kinase Anchor Proteins; D048868:Adaptor Proteins, Signal Transducing / Q000187:drug effects / Q000378:metabolism*; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D019703:Calcineurin / Q000378:metabolism; D006332:Cardiomegaly / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D050778:NFATC Transcription Factors / Q000378:metabolism; D034622:RNA Interference / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D011941:Receptors, Adrenergic / Q000187:drug effects / Q000378:metabolism*; D019837:Ryanodine Receptor Calcium Release Channel / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
D054758:A Kinase Anchor Proteins; D048868:Adaptor Proteins, Signal Transducing; D000318:Adrenergic beta-Agonists; C484293:Akap6 protein, rat; D050778:NFATC Transcription Factors; D011941:Receptors, Adrenergic; D019837:Ryanodine Receptor Calcium Release Channel; D017868:Cyclic AMP-Dependent Protein Kinases; D019703:Calcineurin