Nitric oxide (NO), 1 a ubiquitous multifunctional mediator, is synthesized by nitric-oxide synthases (NOS) during the oxidation of L-arginine to L-citrulline. In the central and peripheral nervous system, skeletal muscle, the macula densa of the kidney, testis, and neutrophils, neuronal NOS (nNOS) is the predominant enzyme for the generation of nitric oxide. NO, synthesized by nNOS, acts as neurotransmitter, neuromodulator, or intracellular signaling molecule. It is involved in synaptic plasticity, regulation of gene expression, development, differentiation, and regeneration and plays an important role in neurodegenerative disorders and stroke as a mediator of neurotoxicity (for review see Refs. 1-4). In the gastrointestinal tract NO generated by nNOS acts as an important mediator of the non-adrenergic non-cholinergic inhibitory innervation of intestinal smooth muscle (5) and as a neuromodulator within the enteric nervous system (6).Although the transcriptional regulation of the other two NOS enzymes, the calcium-dependent endothelial NOS and the calcium-independent inducible NOS, are extensively studied (for review see Refs. 3,7,8), little is known about the transcriptional regulation of the nNOS gene (3, 4, 9, 10), which is considered to be responsible for the largest proportion of NO in the body (1). Although usually named constitutive, recent observations suggest a tightly regulated gene expression of nNOS in response to different physiological and pathophysiological stimuli, resulting in an up-or down-regulation of nNOS mRNA (3, 9).Recently nine distinct first exons, called exons 1a-1i, of nNOS mRNA have been identified, leading to nNOS mRNA variants with different 5Ј-untranslated regions and translational efficiencies (11). The nNOS gene is therefore believed to be one of the most complex genes known in terms of first exon usage and alternative splicing (11)(12)(13). It has been shown that nNOS exons 1c (12) and 1f and 1g (13) (former called exons 1 5Ј3 , 1 5Ј2 , and 1 5Ј1 , respectively), which show high abundant expression in the human gastrointestinal tract (12), are driven by separate promoters in HeLa cells. The use of multiple alternative promoters allows a cell-, tissue-, and site-specific transcriptional regulation of nNOS in different physiological and pathophysiological stages.An altered expression or biological activity of nNOS has been linked to several physiological conditions, like aging and pregnancy, as well as different pathophysiological conditions and diseases such as ischemia/hypoxia and injuries of the central nervous system, inherited diabetes insipidus, heart failure, arteriosclerosis, achalasia, diabetic gastroparesis, and hypertrophic pyloric stenosis (1-4, 7, 14 -17). nNOS␣ mutant mice, * This work was supported by Deutsche Forschungsgemeinschaft Sonderforschungsbereich 391 C5, KKF TU Munich F71-98 and F47-01.
