First 11 pages of thesis. - OPUS - Universität Würzburg

inding to other proteins and sub cellular localization. In neurons, nNOS is
associated with the rough endoplasmic reticulum and the synaptic
membrane 107, 108 whereas in skeletal muscle, nNOS localizes to the
sarcolemma 109 . Some studies have also shown the localization of nNOS
protein in the cytosol 110-112 . The localization of nNOS differs depending on the
cellular compartment or the pathophysiological conditions.
The gene structure and the expressional regulation of nNOS are highly
complex. The expression of nNOS is tightly regulated by post-transcriptional
and post-translational mechanisms. Several nNOS mRNA species are
expressed in different tissues in a developmentally regulated manner. Post-
transcriptional regulation of nNOS involves multiple promoter usage, alternate
splicing through deletion and insertion of exons, varied sites for 3’ untranslated
region cleavage and polyadenylation. The alternative splicing results in the
generation of nNOS proteins which differ in their structural features and catalytic
activity. The full length nNOS protein, nNOS-α has high catalytic activity and is
coded by multiple transcripts 113 . Two additional splice variants of nNOS, the
nNOS-β and nNOS-γ lack the PDZ domain. The nNOS-β and the nNOS-γ
variants have about 80% and 30% of the catalytic activity of full length nNOS-α,
respectively. Because of the lack of the PDZ domain, which is responsible for
targeting nNOS to synaptic membranes, nNOS-β is localized to the cytosol 114 .
Another splice variant, nNOS-µ possesses an in-frame insertion of 34 amino
acids between the oxygenase and the reductase domains and has similar
catalytic activity compared to nNOS-α 115 . Alternative splice variants of nNOS
differ in their cellular compartment of expression and serve differential roles
under physiological and pathological conditions.
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