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      Cyclic GMP Synthesis by Human Retinal Pigment Epithelial Cells Is Mainly Mediated via the Particulate Guanylyl Cyclase Pathway

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          Background/Aims: Cyclic 3′,5′-guanosine monophosphate (cGMP), a central molecule in the phototransduction cascade, is also involved in a number of other physiological processes in the retina, like stimulating the absorption of subretinal fluid by activating the retinal pigment epithelium (RPE) cell pump. The aim of this study was to quantify cGMP synthesis by RPE cells and to investigate the role of two separate enzymatic pathways (soluble versus particulate guanylyl cyclase) in its production. Methods: cGMP expression was evaluated by immunochemistry and radioimmunoassay following culture of the D407 RPE cell line in the presence of a nonselective phosphodiesterase inhibitor (IBMX), in combination with the particulate guanylyl cyclase stimulator atrial natriuretic peptide (ANP) or the soluble guanylyl cyclase stimulator sodium nitroprusside (SNP). Results: Stimulation of the particulate guanylyl cyclase in RPE cells with ANP resulted in high intra- and extracellular cGMP levels. Stimulation of the soluble guanylyl cyclase by SNP resulted in a slight elevation of cGMP levels compared to controls. Conclusions: These results show that cultured human RPE cells are capable of producing cGMP and that most cGMP is generated following stimulation of the particulate guanylyl cyclase pathway.

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          Most cited references 14

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          Cyclic nucleotide-dependent protein kinases: intracellular receptors for cAMP and cGMP action.

          Intracellular cAMP and cGMP levels are increased in response to a variety of hormonal and chemical stimuli; these nucleotides play key roles as second messenger signals in modulating myriad physiological processes. The cAMP-dependent protein kinase and cGMP-dependent protein kinase are major intracellular receptors for these nucleotides, and the actions of these enzymes account for much of the cellular responses to increased levels of cAMP or cGMP. This review summarizes many studies that have contributed significantly to an improved understanding of the catalytic, regulatory, and structural properties of these protein kinases. These accumulated findings provide insights into the mechanisms by which these enzymes produce their specific physiological effects and are helpful in considering the actions of other protein kinases as well.
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            Molecular cloning of a retina-specific membrane guanylyl cyclase.

            We have isolated and characterized cDNA clones encoding the human retinal guanylyl cyclase (retGC), a novel member of the membrane guanylyl cyclase gene family. Like other membrane guanylyl cyclases, the 1101 aa retGC is predicted to have a hydrophobic amino-terminal signal sequence followed by a large extracellular domain, a single membrane spanning domain, a kinase homology domain, and a guanylyl cyclase catalytic domain. In contrast to other membrane guanylyl cyclases, such as natriuretic peptide receptors, retGC has a relatively high basal level of activity when expressed in human 293 cells. cGMP production by retGC is unaffected by any of the known natriuretic peptides. In situ hybridization analysis of a variety of rhesus monkey tissues showed retGC transcripts to be localized exclusively along the retinal outer nuclear layer, corresponding to the nuclei of the rod and cone photoreceptor cells. Our results suggest that retGC may synthesize cGMP required for recovery of the dark state after phototransduction.
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              cGMP-gated conductance in retinal bipolar cells is suppressed by the photoreceptor transmitter.

              Transmitter release from photoreceptors is decreased by light, resulting in a conductance increase in depolarizing bipolar cells. Addition of exogenous cGMP through a patch pipette to depolarizing bipolar cells from slices of dark-adapted tiger salamander retina resulted in an enhancement of the light response. This enhancement was blocked by GTP-gamma-S and dipyridamole, an inhibitor of phosphodiesterase. GTP-gamma-S and dipyridamole also blocked responses to exogenously applied 2-amino-4-phosphonobutyrate (APB), the glutamate agonist selective for this receptor. These data support the hypothesis that the postsynaptic receptor is linked via a G protein to a phosphodiesterase. The binding of glutamate or APB to the receptor suppresses a cGMP-activated current by increasing the rate of cyclic nucleotide hydrolysis.

                Author and article information

                Ophthalmic Res
                Ophthalmic Research
                S. Karger AG
                January 2007
                15 December 2006
                : 39
                : 1
                : 55-59
                aDepartment of Ophthalmology, Eye Research Institute Maastricht, University Hospital Maastricht, and bEuropean Graduate School of Neuroscience, Psychiatry and Neuropsychology, University of Maastricht, Maastricht, The Netherlands
                98015 Ophthalmic Res 2007;39:55–59
                © 2007 S. Karger AG, Basel

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                Page count
                Figures: 1, Tables: 1, References: 28, Pages: 5
                Original Paper


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