Neuronal NOS: Gene Structure, mRNA Diversity, and Functional Relevance

Neuronal nitric oxide synthase (nNOS) has been implicated in a wide variety of physiological and pathological processes. These include neurotransmission, neurotoxicity, skeletal muscle contraction, sexual function, body fluid homeostasis and atherosclerosis, among others. Consistent with the involvement of nNOS in such varied aspects of cellular biology, nNOS mRNA and protein are expressed in numerous tissues. Both its gene structure and expressional regulation are exceedingly complex. Characterization of the genomic organization of the human nNOS has revealed that the transcription unit of 29 exons spans a region greater than 240 kb at 12q24.2. The gene produces multiple mRNA transcripts via a variety of intriguing mechanisms: alternate promoter usage, alternative splicing, cassette insertions/deletions, and varied sites for 3'-UTR cleavage and polyadenylation. Allelic diversity in mRNA structure also exists. Some, but not all, of these various transcripts affect the encoded amino acid sequence and translate into nNOS protein isoforms with altered structural and functional properties. Interestingly, much of this diversity is restricted to the untranslated regions of the mRNA transcript and may affect its translation or stability. Taken together, these properties present nNOS as one of the most complex human genes described to date. Given the importance of nNOS in human health and disease, understanding this intricate genetic regulation has been a major focus in nNOS research. This review addresses the structure of the nNOS gene, its mRNA diversity, and overall genetic regulation with an emphasis on their biological implications.