Nitric Oxide-cyclic GMP Signaling Research Articles

Distribution of nitric oxide synthase and nitric oxide-receptive, cyclic GMP-producing structures in the rat brain

The structures capable of synthesizing cyclic GMP in response to nitric oxide in the rat brain were compared relative to the anatomical localization of neuronal nitric oxide synthase. In order to do this, we used brain slices incubated in vitro, where cyclic GMP-synthesis was stimulated using sodium nitroprusside as a nitric oxide-donor compound, in the presence of the phosphodiesterase inhibitor isobutylmethylxanthine. Nitric oxide-stimulated cyclic GMP synthesis was found in cells and fibers, but was especially prominent in varicose fibers throughout the rat brain. Fibers containing the nitric oxide-stimulated cyclic GMP production were present in virtually every area of the rat brain although there were large regional variations in the density of the fiber networks. When compared with the localization of nitric oxide synthase, it was observed that although nitric oxide-responsive and the nitric oxide-producing structures were found in similar locations in general this distribution was complementary. Only occasionally was nitric oxide-mediated cyclic GMP synthesis observed in structures which also contained nitric oxide synthase. We conclude that the nitric oxide-responsive soluble guanylyl cyclase and nitric oxide synthase are usually juxtaposed at very short distances in the rat brain. These findings very strongly support the proposed role of nitric oxide as an endogenous activator of the soluble guanylyl cyclase in the central nervous system and convincingly demonstrate the presence of the nitric oxide–cyclic GMP signal transduction pathway in virtually every area of the rat brain.

Geometric considerations of nitric oxide–cyclic GMP signalling in the glomerular neuropil of the locust antennal lobe

Using NADPH–diaphorase staining as a marker for nitric oxide (NO) synthase and an antiserum against cyclic GMP, we recently reported the anatomical distribution of nitric oxide donor and target cells in the antennal lobe, the principal olfactory neuropile of the locust. The most striking NADPH–diaphorase activity in the olfactory pathway is concentrated in a cluster of intensely stained local interneurons innervating the glomeruli. After incubation of tissue in a nitric oxide donor and inhibition of phospodiesterase activity, neurons of this cluster expressed cyclic GMP–immunoreactivity in the cell body and neurites. Here we examine the importance of the arrangement of NO donor and target cells for information processing in the glomeruli. The cellular organization of the NO–cyclic GMP system in olfactory interneurons, and the dendritic branching pattern, suggest that nitric oxide may not only act as intercellular, but also as intracellular messenger molecule in the glomerular neuropile of the antennal lobe.

Regulation of nitric oxide-cyclic GMP signalling by metabotropic glutamate receptor and protein kinase c in rat cerebellum

Regulation of nitric oxide-cyclic GMP signalling by metabotropic glutamate receptor and protein kinase c in rat cerebellum

Carbon Monoxide: An Endogenous Modulator of the Nitric Oxide–Cyclic GMP Signaling System

Carbon monoxide (CO) is an activator of soluble guanylyl cyclase and is implicated as a neuronal messenger. CO production, nitric oxide synthase (NOS) activity, and guanosine 3′,5′-monophosphate (cGMP) levels were quantitated in cerebellar granule cell cultures. Metabolic labeling experiments enabled the direct measurement of neuronal CO production in vitro. CO production is significant, and peaked during early stages of culture. NOS activity and cGMP levels synchronously increased as cells matured. Whereas inhibition of NOS depleted cGMP in mature cultures, inhibitors of CO production potentiated the nitric oxide (NO)-mediated cGMP increase. Exogenous CO at similar concentrations to endogenous levels blocked the NO-mediated cGMP increase. These results directly demonstrate that endogenous neuronal CO production is high and indicate that while NO is the major regulator of cGMP in these neurons, CO may modulate the NO–cGMP signaling system.

13] Nitric oxide-cyclic GMP signal transduction system

This chapter provides an overview of nitric oxide (NO)–guanylate cyclase–cyclic guanosine monophosphate (cGMP) signal transduction and discusses its physiological significance. The methods used extensively to study and elucidate the mechanisms involved in cellular communication mediated by this pathway is discussed; these include assays for detecting the enzymatic formation of NO and its coproduct L -citrulline, and purification and assay of soluble guanylate cyclase. The NO–guanylate cyclase–cGMP transduction system represents a remarkable example of how a multitude of cellular responses to a multiple array of biological messengers can be mediated by a single signaling system. The role of NO as an inter- and intracellular messenger molecule, coupled with the identification of the atrial natriuretic peptides (ANPs) as activators of a second, membrane-bound isoform of guanylate cyclase, have further elevated the significance of cGMP as a second messenger. The spectrum of biological effects mediated by NO and cGMP include diverse actions such as anticoagulation, nonadrenergic-noncholinergic (NANC) neurotransmission, phototransduction, and vascular and nonvascular smooth muscle relaxation.

Muscarinic cholinergic stimulation of the nitric oxide-cyclic GMP signaling system in cultured rat sensory neurons

Acetylcholine or carbachol stimulated cyclic GMP production in neuronal cultures from embryonic rat dorsal root ganglia but not in non-neuronal dorsal root ganglia cultures. Acetylcholine stimulation of cyclic GMP production was mediated by muscarinic receptors and required extracellular Ca 2+. Basal cyclic GMP production and acetylcholine-evoked cyclic GMP production were attenuated by Methylene Blue, suggesting the involvement of soluble guanylate cyclase and nitric oxide synthase. l- N G-Monomethyl arginine attenuated basal, acetylcholine or carbachol-stimulated cyclic GMP production; this inhibition of acetylcholine and carbachol stimulation of cyclic GMP was reversed by l-arginine. These results suggest that a nitrosyl factor mediates basal, as well as acetylcholine- and carbachol-stimulated, cyclic GMP production. Selective destruction of small diameter neurons by capsaicin pretreatment of dorsal root ganglion neuronal cultures abolished acetylcholine and capsaicin stimulation of cyclic GMP, but did not affect sodium nitroprusside stimulation of cyclic GMP. These results suggest that acetylcholine evoked production of a nitrosyl factor in capsaicin-sensitive (small diameter) sensory neurons, which subsequently stimulated a soluble guanylate cyclase and cyclic GMP production in adjacent neuronal and/or non-neuronal cells. These results demonstrate that muscarinic agonists stimulate the nitric oxide-cyclic GMP signalling system in capsaicin-sensitive sensory neurons. Thus, the noxious character of acetylcholine when administered peripherally may be mediated by nitric oxide-cyclic GMP.

Regulation of Cytosolic Guanylyl Cyclase by Nitric Oxide: The NO-Cyclic GMP Signal Transduction System

The understanding of guanylyl cyclase regulation by nitrovasodilators has provided a great deal of information explaining the mechanisms of action of these cardiovascular drugs that have been in clinical use for the past century. The biochemical characterization of guanylyl cyclases and their regulation by NO have also permitted us, and others, to understand the mechanism of action of endothelium-dependent vasodilators and, subsequently, the roles for the nitric oxide-cyclic GMP signal transduction system in numerous cells and tissues. The potential importance of this signal transduction cascade is probably not fully appreciated since numerous additional studies obviously need to be performed. Also, as in many areas of science, serendipitous experiments and observations have added critical data to our present understanding in this field.

The nitric oxide-cyclic GMP signalling pathway in rat brain

Nitric oxide is a novel signalling molecule in the brain and a potent activator of the cyclic GMP-synthesising enzyme, soluble guanylate cyclase. To determine if stimulation of cyclic GMP formation is a widespread mechanism of nitric oxide signal transduction, we have compared the distribution of the nitric oxide-generating enzyme (nitric oxide synthase) with that of nitric oxide-stimulated cyclic GMP accumulation, throughout the rat brain. The former was done using NADPH diaphorase histochemistry and the latter by cyclic GMP immunohistochemistry following perfusion of the nitric oxide donor, nitroprusside, in vivo. At a gross level, there was generally a good match when the two were compared in adjacent sections. Although the relative staining intensity varied from area to area, in no grey matter region did we observe cyclic GMP accumulation in the absence of nitric oxide synthase staining. In detail, the locations were complementary rather than identical. In some areas, nitric oxide synthase was found in postsynaptic structures and cyclic GMP accumulation in presynaptic elements and fibres; in others, the locations were reversed. Glial cells and their processes also accumulated cyclic GMP in the cerebellum. The results suggest that soluble guanylate cyclase is a major nitric oxide “receptor” throughout the brain. They also support the hypothesis that nitric oxide generated therein primarily functions as a mediator of cell-cell signalling rather than as a conventional second messenger acting within the cells in which it is produced. The types of communication subserved by nitric oxide appear to be extraordinarily diverse.

IL-4 - The nitric oxide-cyclic GMP signal transduction system for intercellular and intracellular communication.

IL-4 - The nitric oxide-cyclic GMP signal transduction system for intercellular and intracellular communication.

The nitric oxide-cyclic GMP signal transduction pathway in vascular smooth muscle preparations and other tissues

The nitric oxide-cyclic GMP signal transduction pathway in vascular smooth muscle preparations and other tissues