CGMP synthase

The Ca2+-calmodulin complex may also activate nitric oxide synthase (NOS), which binds to a PDZ domain of PSD-95. Activated NOS produces NO from arginine NO, in turn, activates guanylate cyclase, the enzyme that catalyzes the conversion of GTP to the intracellular messenger cGMP, which activates protein kinase G (PKG). 

Fig. 4.1. Cellular model illustrating cell types in vascular wall involved in vasorelaxation induced by SERMs. Putative targets of SERMs are indicated within cyan tags. SERMs directly affect L-type VDCC, BK fil subunit in smooth muscle cells, and ER in endothelial cells. L-type VDCC L-type voltage-dependent calcium channel BK calcium-activated large conductance K+ channel PKG protein kinase G eNOS endothelial nitric oxide synthase GC soluble guanylate cyclase cGMP cyclic GM P V electrochemical membrane potential ER estrogen receptor. See text for further details...

Although NO does not itself use a G-protein for signalling, the mechanism of NO production in vascular endothelium is initiated by IP3 via a G-protein-linked acetylcholine receptor on the cell surface. The IP3 causes activation of nitric oxide synthase via calcium- calmodulin and the NO generated diffuses from the endothelial cell into the adjacent smooth muscle cell where cGMP is produced. 

Reiativeiy recentiy, the gases nitric oxide (NO) and carbon monoxide (CO) have been found to act as neurotransmitters in the nervous system. Nitric oxide is synthesized from L-arginine via nitric oxide synthase, requiring NADPH as a co-enzyme and tetrahydrobiopterin as a cofactor. Unlike other neurotransmitters, NO is a smaii, very soiubie moiecuie and cannot be stored in synaptic vesicles. Rather, it is synthesized on demand and freeiy diffuses through membranes. It is not broken down enzymaticaiiy because it is unstabie and degrades rapidiy. NO may have several actions, one of which is to increase the production of cGMP by guanyiyi... 

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.

Stimulation of NO synthase leads to activation of a NO-sensitive guanylyl cyclase. The associated increase in the cGMP level has multiple consequences. The cGMP can stimulate cGMP-dependent protein kinases it can also open cGMP-controUed ion channels. As a consequence, an increase in the intracellular Ca concentration takes place and a Ca signal is produced. NO can influence both protein phosphorylation and InsPs/diacylglycerol and Ca metabolism by this mechanism and activate a broad palette of biochemical reactions in the cell. 

Schematic illustration of the interrelationships between glutamate and NO in synaptic function in the cetebellum. The presynaptic nerve terminal synthesizes, stores, and releases glutamate (G) as the neurotransmitter by exocytosis as illustrated. The glutamate diffu.ses across the synaptic cleft and interacts with postsynaptic NMDA recepti>rs ( ) that are coupled to calcium (Ca ) channels. Ca influx occurs and the free intracellular Ca complexes with calmtxlulin and activates NO synthase. NADPH is also required hir conversion, and the products of the reaction are NO plus L-citrulline. NO diffuses out of the piistsynaptic cell to interact with nearby target cells, one of which is the presynaptic neuron that released the glutamate in the first place. NO stimulates cytosolic guanylate cyclase and cyclic GMP (cGMP) formation presynaptically, hut the consequence of this pre.synaptic modification is unknown.

Synthesis and reactions of nitric oxide (NO). l-NMMA inhibits nitric oxide synthase. NO complexes with the iron in hemoproteins (eg, guanylyl cyclase), resulting in the activation of cGMP synthesis and cGMP target proteins such as protein kinase G. Under conditions of oxidative stress, NO can react with superoxide to nitrate tyrosine. 

Furthermore, the LPS signal transduction involves the activation of G proteins, of phospholipases C and D, the formation of diacyl-glycerol (DG) and inositol triphosphate (IP3). DG mediates the stimulation of protein kinase C (PKC) and IP3 induces an increase of cytosolic Ca++ The LPS signaling pathway also involves tyrosine kinases, constitutive nitric oxide (NO) synthase (cNOS), cGMP-dependent protein kinase, Ca channels, calmodulin and calmodulin kinase [27,28], as well as the MAP kinases [29] ERK1, ERK2 and p38 [23], The intracellular events in response to LPS are due to lipid A because they are inhibited by polymyxin B which is known to bind lipid A [27] and they are reproduced by lipids A [30,31]. 

Nitric oxide generation from L-arginine and nitric oxide donors and the formation of cGMP. L-NMMA inhibits nitric oxide synthase. Some of the nitric oxide donors such as furoxans and organic nitrates and nitrites require a thiol cofactor such as cysteine or glutathione to form nitric oxide. 

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