[Frontiers in Bioscience 14, 1-18, January 1, 2009]

Discovery of the nitric oxide signaling pathway and targets for drug development

Nathan S. Bryan1, Ka Bian1,2, Ferid Murad1,2

1Institute of Molecular Medicine, The University of Texas-Houston Health Sciences Center, Houston, TX 77030, USA,2The Murad Research Institute for Modernized Chinese Medicine and E-Research Institute of Nitric oxide and Inflammatory Medicine of Shanghai Universities, 1200 Cailun Rd. Shanghai, China

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. Discovery of NO
3.1. Nitric oxide and the Nobel prize
3.2. NO generation and nitric oxide synthase
3.2.1. eNOS
3.2.2. iNOS
3.2.3. nNOS
3.3. Nitrovasodilators
4. NO based cell signaling
4.1. cGMP dependent signaling
4.2. PDE inhibitors
4.3. Splice forms
4.4. Allosteric regulators of sGC
5. cGMP independent signaling
5.1. Nitrite and nitrate
5.2. Nitrosothiols
5.3. Nitrotyrosine
6. Rationale design and development of therapeutics
6.1. Endothelium centered healthy environment for vasculature
6.2. NO-cGMP dependent vasodilator extracted from plants
6.3. Inflammatory diseases & NOS-2 Selective Inhibition
7. Summary
8. References

1. ABSTRACT

Nitric oxide is a multifunctional signaling molecule, intricately involved with maintaining a host of physiological processes including but not limited to host defense, neuronal communication and the regulation of vascular tone. Many of the physiological functions first ascribed to NO are mediated through its primary receptor, soluble guanylyl cyclase. Endogenous production of NO is a highly complex and regulated process involving the 5-electron oxidation of L-arginine requiring numerous substrates and cofactors. The production of a highly reactive and diffusible free radical gas further complicates our established concept and model of specific and targeted receptor-ligand interaction to elicit cell signaling events. Hence there are many steps in the endogenous pathway for altered production of NO and subsequent activation of sGC that may be targets for drug development as well as other molecular targets for NO. The following review will highlight the current state of the art of NO-sGC research and illustrate disease processes which may benefit from novel drug development exploiting the NO-sGC pathway as well as NOS & cGMP-independent pathways.