Oxidants, which can be produced in cells and tissues, have been causatively implicated in the pathogenesis of most major diseases.
Whilst this paradigm is still prevalent, and oxidants may indeed play important roles in the disease etiology, it is now also understood that they can also serve as regulatory entities that are important for the maintenance of homeostasis during health and disease. Oxidants can be sensed and transduced into a biological event via their reaction with select cysteine thiol side chains on some proteins. Such reactions can result in oxidative post-translational modifications of proteins that in some cases alter their function to enable adaptation and homeostasis.
Protein kinase A (PKA) and protein kinase G (PKG) are cyclic nucleotide-dependent kinases, being activated by the second messenger cAMP or cGMP respectively. The Regulatory RIasubunit of PKA and the PKG Iaisoform are each able to form homo interprotein disulfides in response to increased oxidants. These oxidative modifications alter the function of PKA and PKG and have a complex interrelationship with their cyclic nucleotide-dependent regulation. Comparing PKA C17S RIaor C42S PKG Iatransgenic knock-in mice, engineered so that the they cannot form the interprotein disulfides, to wild-type controls has allowed the importance of these oxidative modifications to be defined in terms of cardiovascular function.