Intracellular signaling nitric oxide

Fimiani C, Liberty T, Aquirre AJ, Amin I, Ali N, Stefano GB (1999a) Opiate, cannabinoid, and eicosanoid signaling converges on common intracellular pathways nitric oxide coupling. Prostaglandins Other Lipid Mediat 57 23-34... 

Grb-2 facilitates the transduction of an extracellular stimulus to an intracellular signaling pathway, (b) The adaptor protein PSD-95 associates through one of its three PDZ domains with the N-methyl-D-aspartic acid (NMDA) receptor. Another PDZ domain associates with a PDZ domain from neuronal nitric oxide synthase (nNOS). Through its interaction with PSD-95, nNOS is localized to the NMDA receptor. Stimulation by glutamate induces an influx of calcium, which activates nNOS, resulting in the production of nitric oxide. 

Nitric oxide (NO) is an intercellular signaling molecule that can inhibit neuronal energy production (Brorson et al., 1999 Malefic et al., 2004). It has been found that NO donors cause large increases in extracellular adenosine in cultures of forebrain neurons (Rosenberg et al., 2000). These were shown to be caused by NO release, and the accumulation of adenosine was not blocked by probenecid (ENT blocker) or GMP (a blocker of AMP hydrolysis), suggesting that adenosine was likely of intracellular origin. Indeed, it was found that NO donors caused a decrease in intracellular ATP and the inhibition of adenosine kinase activity, possibly due to the rise in adenosine. 

Three phases of receptor-mediated signaling can be identified 178 Four distinct molecular mechanisms that link agonist occupancy of cell-surface receptors to functional responses have been identified 178 Cross-talk can occur between intracellular signaling pathways 179 Signaling molecules can activate gene transcription 181 Nitric oxide acts as an intercellular signaling molecule in the central nervous system 181... 

Bastian, N. R., Yim, C.-Y., Hibbs, J. B., and Samlowski, W. E. (1994). Induction of iron-derived epr signals in murine cancers by nitric oxide—Evidence for multiple intracellular targets. . Biol. Chem. 269, 5127-5131. 

The signal transduction mechanisms triggered by binding of ET-1 to its vascular receptors include stimulation of phospholipase C, formation of inositol trisphosphate, and release of calcium from the endoplasmic reticulum, which results in vasoconstriction. Conversely, stimulation of PGI2 and nitric oxide synthesis results in decreased intracellular calcium concentration and vasodilation. 

The CNS contains a substantial amount of nitric oxide synthase (NOS), which is found within certain classes of neurons. This neuronal NOS is an enzyme activated by calcium-calmodulin, and activation of NMDA receptors, which increases intracellular calcium, results in the generation of nitric oxide. Although a physiologic role for nitric oxide has been clearly established for vascular smooth muscle, its role in synaptic transmission and synaptic plasticity remains controversial. Perhaps the strongest case for a role of nitric oxide in neuronal signaling in the CNS is for long-term depression of synaptic transmission in the cerebellum. 

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]. 

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