NO as a signalling molecule in the nervous system.

Abstract

The discovery that nitric oxide (NO) functions as a signalling molecule in the nervous system has radically changed the concept of neural communication. Indeed, the adoption of the term nitrergic for nerves whose transmitter function depends on the release of NO or for transmission mechanisms brought about by NO (Moncada et al., 1997) emphasizes the specific characteristics of this mediator. The physical properties of NO prevent its storage in lipid-lined vesicles and metabolism by hydrolytic degradatory enzymes. Therefore, unlike established neurotransmitters, NO is synthesized on demand and is neither stored in synaptic vesicles nor released by exocytosis, but simply diffuses from nerve terminals. The distance of this NO diffusion (40 – 300 μm in diameter) implies that structures in the vicinity of the producing cell, both neuronal and non-neuronal, are influenced following its release. This suggests that, as well as acting as a neurotransmitter, NO has a neuromodulatory role (Garthwaite & Boulton, 1995). In addition, it diffuses into rather than binds with protein receptors on adjacent cells, and most of its known actions are the consequence of interplay with intracellular targets that would usually be regarded as secondary messengers. The activity of conventional neurotransmitters is terminated either by re-uptake mechanisms or enzymatic degradation while inactivation of NO follows reaction with a substrate. There are multiple points at which biological control can be exerted over the production and activity of conventional neurotransmitters. However, control of the synthesis of NO is the key to regulating its activity. Endothelial NOS (eNOS) and inducible NOS (iNOS) are present in the nervous system and will be duly addressed here. However, neuronal NOS (nNOS) is the principal isoform present in said system and will be the main focus of this review. All nNOS positive neurones exhibit α-nicotinamide adenine dinucleotide phosphate (NADPH)-diaphorase activity, which has become the histochemical marker of nitrergic neurones. However, early results demonstrating this may have been limited by inappropriate fixation procedures and should be viewed with caution (Wolf, 1997). The original cloning of full-length nNOS produced what is now designated as nNOSα, and which accounts for the majority of nNOS activity in nervous tissue (Bredt et al., 1991). In addition, four splice variants have recently been identified (nNOSβ, nNOSγ, nNOSμ and nNOS-2) and these appear to exhibit distinct cellular and tissue locations (Gibson, 2001; Nakane et al., 1993; Silvagno et al., 1996; Alderton et al., 2001). In particular, there is growing evidence that nNOS biosynthesis in excitable tissues is not restricted to neurones while substantial amounts of this enzyme have been identified in skeletal muscle, where it is involved in the regulation of metabolism and muscle contractility (Stamler & Meissner, 2001). The magnitude of literature dealing with the role of NO in the nervous system is so great that it would be impossible to include in this review the entirety of the research carried out. For logistical reasons, only groundbreaking references have been quoted, but when necessary, recent reviews dealing with specific areas within the field have been included and are intended to act as a guideline for further reading.