Nos1

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Location

The human gene NOS1, found on chromosome 12, encodes for a nitric oxide synthase which is ubiquitously expressed. Nitric oxide synthases consume L-arginine to produce nitric oxide. The chemical equation is shown below.

2 L-arginine + 3 NADPH + 4 O(2) = 2 L- citrulline + 2 nitric oxide + 3 NADP(+) + 4 H(2)O

Nitric oxide is used in a wide variety of processes. A few examples of molecular processes include heme binding, NADP binding, calcium signaling, and oxidation-reduction reactions. Biological examples include regulation of cardiac muscle contraction, blood coagulation, aging, and regulation of neurogenesis ^[3]. There are three known isoforms known for NOS1 in humans produced by alternative splicing, as well as four natural transcript variants for NOS1. The alternatively-spliced isoforms are reffered to as neuronal NOS (nNOS or NOS1), endothelial NOS (eNOS or NOS3), and cytokine-inducible NOS (iNOS or NOS2). Moderate expression of NOS1 has been observed in skeletal muscle, brain, testicular, lung, and kidney tissue. Low expression has been observed in heart, adrenal gland, and retinal tissues ^[4].

Function

NOS1 is a major component of the production of Nitric Oxide which Nitric Oxide has important roles in the CNS. Nitric Oxide targets NO receptors on G-cylcase as well as other Nitric Oxide specific receptors. NOS1 is an important component of synaptogenesis, long-term potentiation, neurotransmitter release and synaptic plasticity ^[5].NOS1 is coupled with N-methyl-D-Aspartate (NMDA) receptors in the post-synapse of cells, which allows to the processes to occur. The NMDA receptor binds to PSD95 which than binds to NOS1. After the complex is formed, NDMDA receptor mediated CA2+ influx now regulates the amount of Nitric Oxide is produced by NOS1 ^[6]. NOS1 also contributes in limiting increased oxidative stress in the myocardium, limits systolic and diastolic dysfunction and all prevent a failing heart. NOS1 regulates the reuptake of Ca2+ in sarcoplamisic reticulum (SR). NOS1is shown into the human coronary artery smooth cells and maintains of basal blood flow. NOS1 also controls the parasympathetic and sympathetic regulation of the heart^[7]. NOS1 is important in all functions that help regulate the cardiac muscles^[8]. The ability of Nitric Oxide to self regulate enables NOS1 to control all these major functions. In myocite relaxation, the Nitric Oxide produced by NOS1 facilitates SERCA to increase intracellular CA2+ because if the increase in PKA dependent PLN phosphorylation. NOS1 also regulates cardiac function by the Nitric Oxide produced targets not CA2+ dependent^[9]

Disease

Relevance

Structural highlights

Nos exists as a homodimer. This homodimer consists of two regions. One region is an N-terminal oxygenase domain and the other is a C-terminal reductase. The N-terminal oxygenase domain is an extended beta sheet cage with binding sites for heme and pterin. Nos has a N-terminal catalytic domain with a heme active site. Nos 1 also has a cofactor site nearby for tetrahydrobiopterin (H4B). Nos has a C-terminal reductase domain containing FMN, FAD and NADPH binding sites. Electrons are passed from FAD to FMN and then to the heme. This electron flow is controlled by the binding of CaM and Ca2+ in the linker region between the two major domains. The linker between the oxygenase and reductase domains contains a calmodulin-binding sequence. Nos1 is found in neuronal tissue.