Redox regulation of cGMP-dependent protein kinase Iα in the cardiovascular system

Abstract

Elevated levels of oxidants in biological systems have been historically referred to as "oxidative stress," a choice of words that perhaps conveys an imbalanced view of reactive oxygen species in cells and tissues. The term stress suggests a harmful role, whereas a contemporary view is that oxidants are also crucial for the maintenance of homeostasis or adaptive signaling that can actually limit injury. This regulatory role for oxidants is achieved in part by them inducing oxidative post-translational modifications of proteins which may alter their function or interactions. Such mechanisms allow changes in cell oxidant levels to be coupled to regulated alterations in enzymatic function (i.e., signal transduction), which enables "redox signaling." In this review we focus on the role of cGMP-dependent protein kinase (PKG) Ia disulfide dimerisation, an oxidative modification that is induced by oxidants that directly activates the enzyme, discussing how this impacts on the cardiovascular system. Additionally, how this oxidative activation of PKG may coordinate with or differ from classical activation of this kinase by cGMP is also considered.

Keywords: cGMP; cardio-vascular system; disulfide dimerisation; oxidative modification; protein kinase G.

FIGURE 1

PKG Iα contains three functional domains—an N-terminal leucine zipper, a regulatory and a catalytic. There are three pairs of cysteines, which may form disulfide bridges: C117-C195, C312-C518, and C42-C42.

FIGURE 2

An overview of how PKG Iα disulfide dimerisation integrates a variety of stimuli to induce vasodilation and blood pressure lowering.

FIGURE 3

Overview of the roles of PKG Iα disulfide dimerisation in the development of pathologies in the cardiovascular system.

FIGURE 4

Overview of the complex interaction between cGMP- and oxidant-induced PKG Iα activation mechanisms in the heart.