First 11 pages of thesis. - OPUS - Universität Würzburg

perinuclear/golgi region within the cell 95, 96 . Within the caveolae, eNOS is bound
to caveolin-1 in its inactive form 97 . Calcium influx disrupts the caveolin-1/eNOS
complex and results in eNOS activation 98 . Additionally, dynamin-2 and Hsp-90
interact with eNOS and positively regulate the enzyme’s activity 99, 100 .
Superoxide production by eNOS “uncoupling” is believed to result from
BH4 deficiency rather than L-arginine deficiency 101 . The amount of superoxide
generated by eNOS depends on calcium/calmodulin binding. In the absence of
calcium/calmodulin, eNOS generates low amounts of superoxide and the
activation by calcium/calmodulin increases superoxide production 102 . Heme
blockers like cyanide or imidazole prevent eNOS mediated superoxide
generation during BH4 deficiency. This suggests that eNOS generates
superoxide from the heme containing oxygenase domain 35 . One possible
mechanism by which BH4 deficiency occurs is BH4 oxidation 103 .
1.4.2.2 Neuronal nitric oxide synthase (nNOS)
nNOS is involved in a wide variety of physiological and pathological
processes, including neurotransmission, neurotoxicity, skeletal muscle
contraction, body fluid homeostasis and cardiac function 104 . Though the name
implies the expression of this isoform in neuronal tissues, nNOS is expressed in
epithelial cells, mesanglial cells, skeletal muscle cells and cardiomyocytes. In
the vasculature, nNOS is expressed in endothelial 105 as well as smooth muscle
cells of rat and human origin 106 . nNOS is the largest of the NOS isoforms
containing an additional 300 amino acids at the N-terminus. This domain is
called the PDZ (PSD-95 discs large/ zona occludens -1 homology domain)
domain or disc-large homologous region (DHR), which is essential for nNOS
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