Title:Nitric Oxide Synthase and Cyclooxygenase Pathways: A Complex Interplay in Cellular Signaling
Volume: 23
Issue: 24
Author(s): Andrey Sorokin
Affiliation:
Keywords:
Cyclooxygenase, Prostaglandins, Signaling, nitric oxide releasing NSAID, carcinogenesis, NOS system
Abstract: The cellular reaction to external challenges is a tightly regulated
process consisting of integrated processes mediated by a variety of signaling
molecules, generated as a result of modulation of corresponding biosynthetic
systems. Both, nitric oxide synthase (NOS) and cyclooxygenase
(COX) systems, consist of constitutive forms (NOS1, NOS3 and COX-1),
which are mostly involved in housekeeping tasks, and inducible forms
(NOS2 and COX-2), which shape the cellular response to stress and variety
of bioactive agents. The complex interplay between NOS and COX pathways
can be observed at least at three levels. Firstly, products of NOS and
Cox systems can mediate the regulation and the expression of inducible
forms (NOS2 and COX-2) in response of similar and dissimilar stimulus. Secondly, the reciprocal
modulation of cyclooxygenase activity by nitric oxide and NOS activity by prostaglandins
at the posttranslational level has been shown to occur. Mechanisms by which nitric
oxide can modulate prostaglandin synthesis include direct S-nitrosylation of COX and inactivation
of prostaglandin I synthase by peroxynitrite, product of superoxide reaction with
nitric oxide. Prostaglandins, conversely, can promote an increased association of dynein light
chain (DLC) (also known as protein inhibitor of neuronal nitric oxide synthase) with NOS1,
thereby reducing its activity. The third level of interplay is provided by intracellular crosstalk
of signaling pathways stimulated by products of NOS and COX which contributes significantly
to the complexity of cellular signaling. Since modulation of COX and NOS pathways
was shown to be principally involved in a variety of pathological conditions, the dissection
of their complex relationship is needed for better understanding of possible therapeutic
strategies. This review focuses on implications of interplay between NOS and COX
for cellular function and signal integration.