Nitric-oxide synthases signal transduction pathways

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. 

Cannabinoid receptor agonists stimulate the production and release of nitric oxide (NO) by a CBi receptor-mediated mechanism utilizing one of the NO synthase (NOS) isoforms in neuronal tissues and model cells (see Fimiani et al. 1999a for review). The signal transduction pathway between CBi receptors and neuronal NOS (nNOS) regulation is believed to be important for mediating the effects of A -THC on hypothermia and locomotor activity (but not antinociception), as determined by the absence of these responses in nNOS (-/-) knock-out mice (Azad et al. 2001). NO production was stimulated by anandamide via SR141716-sensitive CBl receptors in rat median eminence shces, but it was not clear from these studies... 

As yet, it has not been possible to pinpoint the exact site of injury to the L-arginine nitric oxide pathway. The defect may lie with the surface receptors, signal transduction, L-arginine deficiency, nitric oxide synthase, tolerance of smooth muscle, physical obstruction to the diffusion of nitric oxide by a thickened intima, or impaired guanylate cyclase activation. However, endogenous guanylate cyclase can be activated by exogenously administered nitric oxide to relax smooth muscle, even when unresponsive to acetyl-... 

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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