Soluble guanylyl cyclase

Synthesized by soluble guanylyl cyclase and particulate guanylyl cyclase from guanosine triphosphate (GTP). Nitric oxide activates soluble guanylyl cyclase to enhance cyclic GMP production that contributes to various NO actions. Cyclic GMP is hydrolyzed by phosphodiesterases. Cyclic GMP binds to and activates cGMP-dependent protein kinase, phosphodiesterases, and Cyclic Nucleotide-regulated Cation Channels. 

Heme (C34H3204N4Fe) represents an iron-porphyrin complex that has a protoporphyrin nucleus. Many important proteins contain heme as a prosthetic group. Hemoglobin is the quantitatively most important hemoprotein. Others are cytochromes (present in the mitochondria and the endoplasmic reticulum), catalase and peroxidase (that react with hydrogen peroxide), soluble guanylyl cyclase (that converts guanosine triphosphate, GTP, to the signaling molecule 3, 5 -cyclic GMP) and NO synthases. 

Krumenacker, J., Hanafy, K. A. and Murad, F. Regulation of nitric oxide and soluble guanylyl cyclase. Brain Res. Bull. 62 505-515, 2004. 

A number of the actions of NO in target cells may be explained by its binding to the haem-containing protein soluble guanylyl cyclase (sGC), an enzyme which generates a second messenger, cyclic GMP (cGMP) from GTP. 

It is interesting that the NPl ferrous-NO complex has the proximal histidine in place, unlike the heme of soluble guanylyl cyclase. 

Fig. 3. Mechanisms of vasocontraction and vasorelaxation in endothelial and smooth muscle cells. COX cyclooxygenase, eNOS endothelial nitric oxide synthase, HO-1 heme oxygenase-1, EET epoxyeicosatrienoic acid, EDHF endothelium-derived hyperpolariz-ing factor, PGI2 prostaglandin I2, NO nitric oxide, CO carbon monoxide, PLC phospholipase C, IP3 inositol 1,4,5-trisphosphate, DAG diacylglycerol, ER/SR endo-plasmic/sarcoplasmic reticulum, AC adenylyl cyclase, cAMP cyclic adenosine monophosphate, sGC soluble guanylyl cyclase, cGMP cyclic guanosine monophosphate.

NOS-containing neurons have a very discrete localization in the CNS, representing only 1% of neuronal cells. However, their axons ramify so extensively that virtually every cell in the brain may encounter a NOS nerve terminal. As a diatomic gas, NO is freely diffusible and thus can readily enter adjacent neuronal cells. Once inside the target cell, NO binds the iron in heme contained within the active site of soluble guanylyl cyclase, activating the enzyme to form cyclic guanosine monophosphate (GMP). The activity of NO is therefore mediated by an enzyme receptor. In neurons, NO is formed in response to calcium influx reminiscent of calcium-dependent exocytotic release of neurotransmitters. 

NO activates soluble guanylyl cyclase to elevate cGMP levels in vascular smooth muscle Vasodilator relaxes other smooth muscle inhalation of NO leads to increased blood flow to parts of the lung exposed to NO and decreased pulmonary vascular resistance Hypoxic respiratory failure and pulmonary hypertension Inhaled gas Toxicity Methemoglobinemia... 

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