Publication Date

2009-01-01

Availability

Open access

Degree Type

Thesis

Degree Name

Master of Science (MS)

Department

Molecular and Cellular Pharmacology (Medicine)

Date of Defense

2009-10-27

First Committee Member

Danuta Szczesna-Cordary - Committee Chair

Second Committee Member

Grace R. Zhai - Committee Member

Third Committee Member

Michael S. Kapiloff - Mentor

Abstract

Myocyte hypertrophy is the major compensatory response of the heart to chronic stress. It is induced by the activation of a network of interdependent, intracellular signaling pathways.1 An important pathway activated during the hypertrophic response is the calcineurin Abeta-NFATc transcription factor pathway.2 Our laboratory has recently discovered that calcineurin Abeta and NFATc transcription factors can associate with the scaffold protein mAKAPbeta.3 mAKAPbeta is a scaffold protein that forms a multimolecular signalosome located to the nuclear envelope of cardiac myocytes. Preliminary data demonstrate that calcineurin Abeta binds to a specific site on mAKAPbeta that lacks any of the consensus calcineurin binding sequences previously described. In this report, it is shown that a peptide, which contains the mAKAPbeta -calcineurin Abeta binding domain, associates with calcineurin Abeta in a calcium/calmodulin dependent manner. In addition, the binding of this mAKAPbeta peptide to calcineurin Abeta has no effect on calcineurin?s phosphatase activity. In fact, calcineurin Abeta bound to this mAKAPbeta peptide is catalytically active and capable of dephosphorylating NFAT. This is novel since other scaffold proteins that associate with calcineurin Abeta have been reported to inhibit its phosphatase activity. Furthermore, in our laboratory it has been shown that mAKAPbeta is required for both the nuclear translocation of NFATc and the induction of myocyte hypertrophy in vitro.4 In this report it is demonstrated that inhibition of calcineurin Abeta association to mAKAPbeta affects NFATc phosphorylation state and attenuates the norepinephrine induced hypertrophic response in primary neonatal cardiac myocytes. This study supports the hypothesis that the formation of multimolecular signaling complexes, like the mAKAPbeta signalosome, is necessary for the integration and fidelity of signal transduction involved in physiological processes like hypertrophy. Although hypertrophy is an adaptive response; it is often accompanied by maladaptive remodeling of the heart that can result in heart failure, a leading cause of death in the United States. Research in the signaling complexes involved in myocyte hypertrophy, like the mAKAPbeta signalosome, may lead to the development of novel treatments for pathologic hypertrophy and heart failure.

Keywords

Hypertrophy; Scaffold; NFAT; Calcineurin; MAKAP

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