Nitric oxide signaling pathways

Epidemiologic, experimental, and in vitro mechanistic data indicate that lead exposure elevates blood pressure in susceptible individuals. In populations with environmental or occupational lead exposure, blood lead concentration is linked with increases in systolic and diastolic blood pressure. Studies of middle-aged and elderly men and women have identified relatively low levels of lead exposure sustained by the general population to be an independent risk factor for hypertension. In addition, epidemiologic studies suggest that low to moderate levels of lead exposure are risk factors for increased cardiovascular mortality. Lead can also elevate blood pressure in experimental animals. The pressor effect of lead may be mediated by an interaction with calcium mediated contraction of vascular smooth muscle, as well as generation of oxidative stress and an associated interference in nitric oxide signaling pathways. 

Xu Y. and Tao Y. X. (2004). Involvement of the NMDA receptor/nitric oxide signal pathway in platelet-activating factor-induced neurotoxicity. NeuroReport 15 263-266. 

Riccio A, Alvania RS, Lonze BE, Ramanan N, Kim T, Huang Y, Dawson TM, et al. (2006) A nitric oxide signaling pathway controls CREB-mediated gene expression in neurons. Mol Cell 21 283-94... 

Figure 1 Nitric oxide signal transduction pathway. NO synthesized by NOS diffuses across cell membranes to a target cell. NO activates sGC, which leads to an increase in cCMP synthesis. The oxidation products of NO also can react with protein thiols, which leads to protein S-nitrosation.

Signal transduction through surface CD23 ligation is linked to cyclic nucleotides and nitric oxide (NO) pathways in various human cells and in rat macrophages (18). Some divergences are found between the signaUng pathways cou-... 

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. 

FIGURE 8.11 Multiple signal-transduction pathways initiated by calmodulin. Calmodulin bound to Ca2+ interacts and activates many enzymes, opening up a wide range of possible cellular responses. Abbreviations MAP-2, microtubule-associated protein 2 NO, nitric oxide Tau, tubulin assembly unit. 

G. Rocchitta, R. Migheli, M.P. Mura, G. Esposito, M.S. Desole, E. Miele, M. Miele, and P.A. Serra, Signalling pathways in the nitric oxide donor-induced dopamine release in the striatum of freely moving rats evidence that exogenous nitric oxide promotes Ca2+ entry through store-operated channels. Brain Res. 1023, 243-252 (2004). 

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... 

A special guanylate cyclase receptor can be found in the nitric oxide (NO) signaling pathway. The activation of the sequence of events in that pathway results in smooth muscle relaxation. This pathway is directly linked to other cascades by receiving a Ca2+ signal and utilizing calmodulin (CaM) as transmitter protein. 

Messmer, U.K. and Brune, B., Nitric oxide-induced apoptosis p53-depedent and p53-inde-pendent signalling pathways, Biochem. J., 319, 299, 1995. 

This review will focus on three main reactions of dilute nitric oxide in physiological solutions. The first reaction is the binding of nitric oxide to ferrous heme iron of guanylate cyclase or other proteins, which is important for the activation of signal transduction pathways. 

The diverse actions of AM are mediated by the 7-transmembrane G protein-coupled calcitonin receptor-like receptor (CRLR) which coassembles with subtypes 2 and 3 of a family of receptor-activity-modifying proteins (RAMPs), thus forming a receptor-coreceptor system. Binding of AM to CRLR activates Gs and triggers cAMP formation in vascular smooth muscle cells, and increases nitric oxide production in endothelial cells. Other signaling pathways are also involved. 

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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