title: Molecular mechanisms underlying cardiac protein phosphatase 2A regulation in heart.
abstract: Kinase/phosphatase balance governs cardiac excitability in health and disease. Although detailed mechanisms for cardiac kinase regulation are established, far less is known regarding cardiac protein phosphatase 2A (PP2A) regulation. This is largely due to the complexity of the PP2A holoenzyme structure (combinatorial assembly of three subunit enzyme from >17 subunit genes) and the inability to segregate "global" PP2A function from the activities of multiple "local" holoenzyme populations. Here we report that PP2A catalytic, regulatory, and scaffolding subunits are tightly regulated at transcriptional, translational, and post-translational levels to tune myocyte function at base line and in disease. We show that past global read-outs of cellular PP2A activity more appropriately represent the collective activity of numerous individual PP2A holoenzymes, each displaying a specific subcellular localization (dictated by select PP2A regulatory subunits) as well as local specific post-translational catalytic subunit methylation and phosphorylation events that regulate local and rapid holoenzyme assembly/disassembly (via leucine carboxymethyltransferase 1/phosphatase methylesterase 1 (LCMT-1/PME-1). We report that PP2A subunits are selectively regulated between human and animal models, across cardiac chambers, and even within specific cardiac cell types. Moreover, this regulation can be rapidly tuned in response to cellular activation. Finally, we report that global PP2A is altered in human and experimental models of heart disease, yet each pathology displays its own distinct molecular signature though specific PP2A subunit modulatory events. These new data provide an initial view into the signaling pathways that govern PP2A function in heart but also establish the first step in defining specific PP2A regulatory targets in health and disease.
authors.affiliation: Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, Ohio 43210, USA.
authors.forename: Sean T
authors.initials: ST
authors.lastname: DeGrande
authors.forename: Sean C
authors.initials: SC
authors.lastname: Little
authors.forename: Derek J
authors.initials: DJ
authors.lastname: Nixon
authors.forename: Patrick
authors.initials: P
authors.lastname: Wright
authors.forename: Jedidiah
authors.initials: J
authors.lastname: Snyder
authors.forename: Wen
authors.initials: W
authors.lastname: Dun
authors.forename: Nathaniel
authors.initials: N
authors.lastname: Murphy
authors.forename: Ahmet
authors.initials: A
authors.lastname: Kilic
authors.forename: Robert
authors.initials: R
authors.lastname: Higgins
authors.forename: Philip F
authors.initials: PF
authors.lastname: Binkley
authors.forename: Penelope A
authors.initials: PA
authors.lastname: Boyden
authors.forename: Cynthia A
authors.initials: CA
authors.lastname: Carnes
authors.forename: Mark E
authors.initials: ME
authors.lastname: Anderson
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Hund
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Mohler
mesh_terms: D000818:Animals; D001483:Base Sequence; D017931:DNA Primers; D004285:Dogs; D006801:Humans; D047468:Immunoprecipitation; D051379:Mice; D009206:Myocardium / Q000201:enzymology*; D016133:Polymerase Chain Reaction; D014176:Protein Biosynthesis; D054648:Protein Phosphatase 2 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014158:Transcription, Genetic
chemical_list: D017931:DNA Primers; D054648:Protein Phosphatase 2