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  • br Soluble guanylyl cyclase nitric

    2022-01-13


    Soluble guanylyl cyclase, nitric oxide and nitric oxide synthase The primary and best-studied endogenous activator of soluble guanylyl cyclase (sGC) is nitric oxide (NO), which was originally describe as endothelium-derived relaxing factor for its potent ability to relax blood vessels in response to vasodilators like Caspase-3/7 Inhibitor or bradykinin [18]. NO is synthesized by nitric oxide synthase (NOS), which catalyzes a NADPH-dependent 5-electron oxidation of L-arginine by O2 to produce NO and citrulline. There are three genetically distinct isoforms of NOS: a constitutively expressed and calcium-activated endothelial form (eNOS or NOS3), a neuronal isozyme (nNOS or NOS1) and a cytokine- or endotoxin-induced, calcium-independent form (iNOS or NOS2) that is highly expressed in macrophages and neutrophils. Endothelium produced NO migrates into blood and surrounding vascular smooth muscle cells to inhibit platelet aggregation and stimulate vasorelaxation, respectively. Blood pressures in mice lacking endothelial NOS are about 20mm of Hg higher than pressures in wild type littermates [19], [20]. Neuronal NOS also causes vasodilation and may be a retrograde messenger in the long-term potentiation process involved in the formation of memories. Mice with disruptions in exon two of nNOS have enlarged pyloric sphincters and increased aggressive behavior, but normal blood pressure [21], [22]. The main role of inducible NOS is to kill invading microorganisms by producing high levels of NO, which combine with superoxide to form peroxynitrite. Thus, the immune function of NO is independent of guanylyl cyclase. Soluble GCs are found in most tissues. Lung, brain, kidney and vascular tissue are rich in sGC. In humans, two α and two β subunits have been identified, but the function of the β2 is uncertain. The best-characterized heterodimers are the α1/β1 and the α2/β1 forms. β1 is 619 residues and contains an evolutionarily conserved amino-terminal heme prosthetic group binding domain of about 200 residues, a dimerization region and a carboxyl-terminal guanylyl cyclase domain of about 250 residues. The β2 subunit has an additional 86 carboxyl-terminal amino acids compared to the β1 isoform that contains a consensus CAAX sequence for possible isoprenylation or carboxymethylation [23]. In contrast to the other subunits, β2 was reported to form an active homodimer [24]. The human α1 subunit is 717 amino acids and is about 34% homologous to the β1 subunit [25]. The α2 subunit is 48% identical to the α1 subunit at the amino acid level [26]. α1 is the major subunit in platelets and lung but only accounts for about half the NO-dependent guanylyl cyclase activity in the brain [27]. Although α2 only represents 6% of the soluble cyclase activity in the vasculature, it is sufficient to yield maximum smooth muscle relaxation in response to NO in mice lacking α1[27]. His-105 at the amino terminus of the β1 subunit is the axial ligand of the pentacoordinated reduced iron center of heme [28]. His-105 and a heme prosthetic group containing reduced iron are required for NO activation of the enzyme. NO activates sGC by binding to the sixth position of the heme ring, which breaks the bond between the axial histidine and iron to form a 5-coordinated ring with NO in the fifth position. Carbon monoxide can also activate sGC by binding heme to form a 6-coordinated complex. However, since NO activates the enzyme 100 to 200 fold whereas CO only activates it about 4-fold. It is unclear if CO signals in a physiologic significance manner. Genetic disruption of the α1 subunit leads to the loss of NO-dependent platelet aggregation but has a normal vasorelaxation response [27]. Disruption of the β1 subunit [29] leads to the loss of both these responses with blood pressures being elevated 26mm of Hg in the knockout compared to wild type animals [29]. In addition, the homozygous knockout animals exhibited severely reduced parastalsis leading to gastrointestinal obstruction similar to that observed in animals lacking cGMP dependent protein kinase I, (PKGI/cGKI) [30]. The male mice lacking the β1 subunit are infertile [30]. In conclusion, sGC appears to be the sole mediator of the major cardiovascular and sexual arousal effects of NO [31].