Roles and regulation of protein phosphatase 2A (PP2A) in the heart

Abstract

Reversible protein phosphorylation is central to a variety of cardiac processes including excitation-contraction coupling, Ca²⁺ handling, cell metabolism, myofilament regulation, and cell-cell communication. While kinase pathways linked with elevated adrenergic signaling have been a major focus for the cardiovascular field over the past half century, new findings support the critical role of protein phosphatases in both health and disease. Protein phosphatase 2A (PP2A) is a central cardiac phosphatase that regulates diverse myocyte functions through a host of target molecules. Notably, multiple mechanisms have evolved to dynamically tune PP2A function, including modulation of the composition, phosphorylation, methylation, and localization of PP2A holoenzyme populations. Further, aberrations in this regulation of PP2A function may contribute to cardiac pathophysiology. In summary, PP2A is a critical regulatory molecule in both health and disease, with a myriad of targets in heart. Based on their unique structure, localization, and regulatory properties, PP2A subunits represent exciting therapeutic targets to modulate altered adrenergic signaling in cardiovascular disease.

Keywords: Arrhythmia; Cardiac disease; Ion channel; PP2A; Protein phosphatases.

Fig. 1

PP2A holoenzyme organization. PP2A holoenzyme, including PP2A-A scaffolding subunit, PP2A-C catalytic subunit, and one or more PP2A-B regulatory subunits. Posttranslational modifications known to modify PP2A-C function are shown. The combinatorial assembly of PP2A subunits confers holoenzyme localization and activity.

Fig. 2

Diversity of cardiac PP2A targets. Summary of key PP2A targets, separated by cellular function. Targets listed in italics indicate dephosphorylation by both PP1 and PP2A.