Alternative Processing: Neuronal Nitric Oxide Synthase

Abstract

The human neuronal nitric oxide synthase (nNOS) gene is expressed from multiple promoters and is subject to alternate messenger ribonucleic acid (mRNA) processing. These complex molecular mechanisms contribute to regulating gene expression and function in multiple tissues and cell types. In the case of nNOS, these distinct promoters give rise to mRNA transcripts with untranslated leader sequences that have differing lengths, nucleotide composition and three‐dimensional structure. These distinct leader sequences have robust effects on translational efficiency. In disease settings, these have functional relevance. For example, in settings of low oxygen content, a unique promoter becomes transcriptionally active. In contrast to basally expressed transcripts, this hypoxia‐induced mRNA is very efficiently translated. To accommodate diverse biological roles, multiple mechanisms have evolved to produce a diverse range of nNOS mRNA transcripts from a single genetic locus.

Key Concepts

  • Mammalian genes can have more than one promoter.
  • Having more than one promoter implies that the gene has more than one version of exon 1.
  • Initiation of transcription in different regions of genomic DNA imparts different nucleotide sequences to the leader regions of messenger ribonucleic acid transcripts, also known as the 5′‐untranslated region (5′‐UTR).
  • Different leader sequences may, or may not, affect protein structure depending on whether the initiator AUG codon for translation of the protein lies in exon 1 or downstream.
  • If multiple versions of exon 1 all have their own initiator AUG codon, then the encoded protein will exist in different forms, each with a unique N‐terminal peptide sequence.
  • Different 5′‐UTRs of messenger ribonucleic acid transcripts can have functional effects on expression of the encoded protein.
  • The 5′‐UTRs of messenger ribonucleic acid transcripts can affect translational efficiency.
  • The 5′‐UTRs of messenger ribonucleic acid transcripts can affect subcellular messenger ribonucleic acid transcript localisation.
  • The 5′‐UTRs of messenger ribonucleic acid transcripts can affect messenger ribonucleic acid transcript stability.
  • Factors that regulate chromatin and transcription complexes can impact the splicing process.

Keywords: alternate promoter usage; mRNA processing; nitric oxide; splicing; epigenetic influence

Figure 1. Alternate promoter usage is one source of 5′‐UTR diversity in human nNOS mRNA transcripts. The varied promoters initiate transcription (right‐pointing arrowheads) of a distinct and separate exon 1 (adjacent boxes Ex 1a, Ex 1b etc.). Each exon 1 splices (diagonal lines) to the common exon 2, which contains the translational start codon (ATG). The nNOS mRNAs differ in the 5′‐UTR region (open boxes) but all encode the same protein because the ORF (shaded boxes) is unaffected. Figure is not to scale.
Figure 2. Hypoxia induces a shortened 5′‐UTR nNOS transcript that is efficiently translated into protein. In normal conditions (a), nNOS transcription is initiated (arrowhead) at an upstream region and encodes a long first exon that is spliced to a common exon 2, where translation initiates. This produces an nNOS mRNA transcript with a long, structured 5′‐UTR that is poorly translated into protein. Under hypoxic conditions (b), nNOS transcription initiates (arrowhead) at downstream regions just upstream of regions encoding exon 2. This generates an mRNA transcript containing a shortened 5′‐UTR that is very efficiently translated into protein. Open box denotes 5′‐UTR. Shaded box denotes open reading frame (ORF).
Figure 3. Examples of varied molecular splicing events resulting in alternately processed transcripts. The genomic locus (top) indicates the intron/exon boundaries; exons are depicted as vertical boxes and introns as the intervening horizontal line. During pre‐mRNA splicing, the introns (diagonal lines) are removed and the remaining exonic sequences are spliced together.
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References

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Further Reading

Brenman JE, Xia H, Chao DS, Black SM and Bredt DS (1997) Regulation of neuronal nitric oxide synthase through alternative transcripts. Developmental Neuroscience 19: 224–231.

Christopherson KS and Bredt DS (1997) Nitric oxide in excitable tissues: physiological roles and disease. Journal of Clinical Investigation 100: 2424–2429.

Forstermann U, Boissel JP and Kleinert H (1998) Expressional control of the ‘constitutive’ isoforms of nitric oxide synthase (NOS I and NOS III). FASEB Journal 12: 773–790.

Wang Y and Marsden PA (1995) Nitric oxide synthases: gene structure and regulation. Advances in Pharmacology 34: 71–90.

Wang Y, Newton DC and Marsden PA (1999) Neuronal NOS: gene structure, mRNA diversity, and functional relevance. Critical Reviews in Neurobiology 13: 21–43.

Web Links

Nitric oxide synthase 1 (neuronal) (NOS1); Gene ID: 4842. Gene: http://www.ncbi.nlm.nih.gov/gene/4842

Nitric oxide synthase 1 (neuronal) (NOS1); MIM number: 163731. OMIM: http://www.ncbi.nlm.nih.gov/omim/163731

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How to Cite close
Steer, Brent M, and Marsden, Philip A(Nov 2016) Alternative Processing: Neuronal Nitric Oxide Synthase. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0005040.pub3]