In cardiac disease, the heart compensates for chronic stress mainly by myocyte hypertrophy. Hypertrophy is induced by signaling through intracellular pathways that include multimolecular protein complexes. The mAKAP signaling complex localizes the cAMP-dependent protein kinase A (PKA), a phosphodiesterase, a protein phosphatase and the ryanodine receptor to the nuclear envelope in cardiac myocytes. We have found that the mAKAP complex plays a role in the induction of myocyte hypertrophy by catecholamines. Preliminary data demonstrates that mAKAP also binds the transcription factor NFATc1 in a regulated manner. We propose that adrenergic stimulation activates ryanodine receptors in the mAKAP complex, releasing calcium that will activate the phosphatase calcineurin. Calcineurin de-phosphorylates and activates the NFATc transcriptions factor family enhancing the transcription of genes involved in hypertrophy. Upon calcineurin activation, NFATc1 is also recruited to the mAKAP complex, where it may be re-phosphorylated by mAKAP-anchored PKA. The goal of this proposal is to characterize the mAKAP/NFATc1 association. I shall examine whether the binding of active NFATc1 to mAKAP constitutes a mechanism by which the activation of NFATc1 can be attenuated, preventing unrestrained hypertrophy. ? ?
