Specificity of a third kind: reactive oxygen and nitrogen intermediates in cell signaling

Abstract

The participation of reactive oxygen intermediates (ROI) and reactive nitrogen intermediates (RNI) in intracellular signaling is widely documented. Nonetheless , it has been difficult to understand how their involvement meets the requirement of signaling for specificity, and hence, to accept that their role could be physiologic. The problem can be resolved by adducing three postulates: (a) to execute and coordinate multiple adaptations to a changing environment , intracellular signaling requires several different types of specificity; (b) based on the chemistry of the mediators, types of specificity can be distinguished by whether an intermediate in a signaling pathway regulates additional pathways that are physically noncon-tiguous with the one in which it was formed, and if it does so, whether it acts like an on/off switch or a rheostat; and (c) a given mediator can have specificity of more than one type. Type I specificity involves intermediary interactions that are initiated noncovalently based on comple-mentarity of molecular shape. Members of a type I signaling pathway are colocalized such that information is private to a given pathway and flows in a linear manner. Type II specificity also involves initial interactions that are based on complementarity, but the mediators diffuse to switch on or off some pathways that are not colocalized with the pathway that generates them. Type III specificity involves covalent interactions as the initial interaction of one signaling intermediate with another. Mediators exerting type III specificity diffuse to affect multiple targets that are not colocalized, where their major function is to regulate how these pathways respond to their own individual agonists. Mediators acting with specifici-ty of types II and III convey information publicly, that is, across much of the cell. ROI and RNI can serve as agonists to activate pathways that operate with type I or type II specificity, but for the most part, endogenous ROI and RNI behave with specificity of the third kind. Looking back and taking stock More than ten years ago, the following "perspective and proposal" was offered in a survey of the rising tide of NO biology: Our understanding of cell-cell communication is dominated by a single paradigm: signaling is accomplished by molecules that bind noncovalent-ly to specific receptors through complementarity of shape. The most surprising insight to arise from NO research is that there exists a fundamentally different form of intercellular signaling. In this new system, the messenger molecule reacts with its targets covalently. .. The latter system may prove to be as ubiquitous and physiologically important as the former. .. It has only recently been appreciated that reactive oxygen intermedi-ates have broad potential to act as secretagogues, enzyme activators and regulators of transcription, along with their more familiar roles as enzyme inactivators, antiseptics, cytotoxins, and muta-gens. Close biochemical and biological parallels between reactive nitrogen intermediates and reac-tive oxygen intermediates prompt the hypothesis that NO may share the ability of ROI to activate proteases, protein tyrosine kinases, protein kinase C, fos, jun, and NF-κB (1). In the intervening years, these predictions were fulfilled for both intercellular and intracellular signaling. The list of signaling molecules known to be regulated by ROI and/or RNI has expanded far beyond the original examples-soluble guanylyl cyclase for RNI (2-4) and NF-κB (5) and activation protein-1 (6) for ROI-to include ion channels and transporters, G protein coupled receptors, small GTPases, phosphatases,