Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:4.6.1.2 (guanylate cyclase)
8,497 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Changes in the Ca2+ concentration are thought to affect many processes, including signal transduction in a vast number of biological systems. However, only in few cases the molecular mechanisms by which Ca2+ mediates its action are as well understood as in phototransduction. In dark-adapted photoreceptor cells, the equilibrium level of cGMP is maintained by two opposing activities, such as phosphodiesterase (PDE) and guanylate cyclase (GC). Upon absorption of photons, rhodopsin-G-protein-mediated activation of PDE leads to a transient decrease in [cGMP] and subsequently to lowering of [Ca2+]. In turn, lower [Ca2+] increases net production of cGMP by stimulation of GC until dark conditions are re-established. This activation of GC is mediated by Ca2+ -free forms of Ca2+ -binding proteins termed GC-activating proteins (GCAPs). The last decade brought the molecular identification of GCs and GCAPs in the visual system. Recent efforts have been directed toward understanding the properties of GC at the physiological and structural levels. Here, we summarize the recent progress and present a list of topics of ongoing research.
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PMID:Photoreceptor guanylate cyclase variants: cGMP production under control. 1473 96

Photoreceptor cells have a remarkable capacity to adapt the sensitivity and speed of their responses to ever changing conditions of ambient illumination. Recent studies have revealed that a major contributor to this adaptation is the phenomenon of light-driven translocation of key signaling proteins into and out of the photoreceptor outer segment, the cellular compartment where phototransduction takes place. So far, only two such proteins, transducin and arrestin, have been established to be involved in this mechanism. To investigate the extent of this phenomenon we examined additional photoreceptor proteins that might undergo light-driven translocation, focusing on three Ca(2+)-binding proteins, recoverin and guanylate cyclase activating proteins 1 (GCAP1) and GCAP2. The changes in the subcellular distribution of each protein were assessed quantitatively using a recently developed technique combining serial tangential sectioning of mouse retinas with Western blot analysis of the proteins in the individual sections. Our major finding is that light causes a significant reduction of recoverin in rod outer segments, accompanied by its redistribution toward rod synaptic terminals. In both cases the majority of recoverin was found in rod inner segments, with approximately 12% present in the outer segments in the dark and less than 2% remaining in that compartment in the light. We suggest that recoverin translocation is adaptive because it may reduce the inhibitory constraint that recoverin imposes on rhodopsin kinase, an enzyme responsible for quenching the photo-excited rhodopsin during the photoresponse. To the contrary, no translocation of rhodopsin kinase itself or either GCAP was identified.
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PMID:Recoverin undergoes light-dependent intracellular translocation in rod photoreceptors. 1596 91

We have recently shown that activation of retinal guanylate cyclase (retGC) by GC-activating proteins (GCAPs) is much stronger than that previously reported and that preincubation of photoreceptor outer segment homogenates with ATP or its analogue, adenylyl imidodiphosphate (AMP-PNP), is required for the strong activation [Yamazaki, A., Yu, H., Yamazaki, M., Honkawa, H., Matsuura, I., Usukura, J., and Yamazaki, R. K. (2003) J. Biol. Chem. 278, 33150-33160]. Here we show that illuminated rhodopsin is essential for development of the AMP-PNP incubation effect. This was demonstrated by illumination of dark homogenates and treatments of illuminated homogenates with 11-cis-retinal and hydroxylamine prior to the AMP-PNP incubation and by measurement of the GCAP2 concentration required for 50% activation. We also found that the AMP-PNP incubation effect was not altered by addition of guanosine 5'-O-(3-thiotriphosphate), indicating that transducin activation is not required. It is concluded that illuminated rhodopsin is involved in retGC activation in two ways: to initiate the ATP incubation effect for preparation of retGC activation as shown here and to reduce the Ca2+ concentrations through cGMP phosphodiesterase activation as already known. These two signal pathways may be activated in a parallel and perhaps proportional manner and finally converge for strong activation of retGC by Ca2+-free GCAPs.
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PMID:Illuminated rhodopsin is required for strong activation of retinal guanylate cyclase by guanylate cyclase-activating proteins. 1646 36

Melanocytes, melanoma and photoreceptor cells are of neuroectodermal origin and have a certain sensitivity to light. In this study, we present evidence for photoreceptor proteins that are responsible for visual transduction and its regulation function as a new class of cancer antigens in melanoma. Visual rhodopsin, transducin, cGMP-phosphodiesterase 6, cGMP-dependent channels, guanylyl cyclase, rhodopsin kinase, recoverin and arrestin are expressed in melanoma and can induce antibody responses in patients. Melanocytes also express mRNA of all photoreceptor genes besides transducin, but were devoid of the corresponding protein, which was tested for rhodopsin, cGMP-phosphodiesterase, guanylyl cyclase and recoverin. Furthermore, we show for the first time that some healthy tissues express mRNA of these genes, but never protein. Expression profiles and autoantibody responses were confirmed in the MT/ret and the HGF(tg)/Ink4a(-/-) transgenic mouse melanoma models. We propose a molecular transition of cancer-retina antigens from mRNA expression in melanocytes to protein expression in melanoma. Our work provides the basis for analyzing regulation of photoreceptor gene expression in normal and malignant cells as well as possible therapeutic tumor targeting using the newly defined class of cancer-retina antigens.
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PMID:Photoreceptor proteins as cancer-retina antigens. 1718 67

Retinal guanylate cyclases 1 and 2 (GC1 and GC2) are responsible for synthesis of cyclic GMP in rods and cones, but their individual contributions to phototransduction are unknown. We report here that the deletion of both GC1 and GC2 rendered rod and cone photoreceptors nonfunctional and unstable. In the rod outer segments of GC double knock-out mice, guanylate cyclase-activating proteins 1 and 2, and cyclic GMP phosphodiesterase were undetectable, although rhodopsin and transducin alpha-subunit were mostly unaffected. Outer segment membranes of GC1-/- and GC double knock-out cones were destabilized and devoid of cone transducin (alpha- and gamma-subunits), cone phosphodiesterase, and G protein-coupled receptor kinase 1, whereas cone pigments were present at reduced levels. Real time reverse transcription-PCR analyses demonstrated normal RNA transcript levels for the down-regulated proteins, indicating that down-regulation is posttranslational. We interpret these results to demonstrate an intrinsic requirement of GCs for stability and/or transport of a set of membrane-associated phototransduction proteins.
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PMID:The function of guanylate cyclase 1 and guanylate cyclase 2 in rod and cone photoreceptors. 1725

Previous experiments indicate that congenital human retinal degeneration caused by genetic mutations that change the Ca(2+) sensitivity of retinal guanylyl cyclase (retGC) can result from an increase in concentration of free intracellular cGMP and Ca(2+) in the photoreceptors. To rescue degeneration in transgenic mouse models having either the Y99C or E155G mutations of the retGC modulator guanylyl cyclase-activating protein 1 (GCAP-1), which produce elevated cGMP synthesis in the dark, we used the G90D rhodopsin mutation, which produces constitutive stimulation of cGMP hydrolysis. The effects of the G90D transgene were evaluated by measuring retGC activity biochemically, by recording single rod and electroretinogram (ERG) responses, by intracellular free Ca(2+) measurement, and by retinal morphological analysis. Although the G90D rhodopsin did not alter the abnormal Ca(2+) sensitivity of retGC in the double-mutant animals, the intracellular free cGMP and Ca(2+) concentrations returned close to normal levels, consistent with constitutive activation of the phosphodiesterase PDE6 cascade in darkness. G90D decreased the light sensitivity of rods but spared them from severe retinal degeneration in Y99C and E155G GCAP-1 mice. More than half of the photoreceptors remained alive, appeared morphologically normal, and produced electrical responses, at the time when their siblings lacking the G90D rhodopsin transgene lost the entire retinal outer nuclear layer and no longer responded to illumination. These experiments indicate that mutations that lead to increases in cGMP and Ca(2+) can trigger photoreceptor degeneration but that constitutive activation of the transduction cascade in these animals can greatly enhance cell survival.
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PMID:Constitutive excitation by Gly90Asp rhodopsin rescues rods from degeneration caused by elevated production of cGMP in the dark. 1769 62

Rod and cone cells of the mammalian retina harbor two types of a membrane bound guanylate cyclase (GC), rod outer segment guanylate cyclase type 1 (ROS-GC1) and ROS-GC2. Both enzymes are regulated by small Ca(2+)-binding proteins named GC-activating proteins that operate as Ca2+ sensors and enable cyclases to respond to changes of intracellular Ca2+after illumination. We determined the expression level of ROS-GC2 in bovine ROS preparations and compared it with the level of ROS-GC1 in ROSs. The molar ratio of a ROS-GC2 dimer to rhodopsin was 1 : 13 200. The amount of ROS-GC1 was 25-fold higher than the amount of ROS-GC2. Heterologously expressed ROS-GC2 was differentially activated by GC-activating protein 1 and 2 at low free Ca2+ concentrations. Mutants of GC-activating protein 2 modulated ROS-GC2 in a manner different from their action on ROS-GC1 indicating that the Ca2+ sensitivity of the Ca2+ sensor is controlled by the mode of target-sensor interaction.
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PMID:Expression level and activity profile of membrane bound guanylate cyclase type 2 in rod outer segments. 1786 28

We discuss putative mechanisms of membrane protein transport in photoreceptors based on Pde6d and Gucy2e/Gucy2f knockout mice. Knockout of the Pde6d gene encoding PrBP/delta, a prenyl binding protein present in the retina at relatively high levels, was shown to impair transport of G-protein coupled receptor kinase 1 (GRK1) and cone phosphodiesterase alpha' subunit (PDE6alpha') to the rod and cone outer segments. Other prenylated proteins are minimally affected, suggesting some specificity of interaction. Knockout of the Gucy2e gene encoding guanylate cyclase 1 (GC1) disrupted transport of G-protein coupled receptor kinase 1 (GRK1), cone PDE6alpha', cone transducin alpha and gamma subunits (cTalpha and cTgamma) to the cone outer segments, while a GC1/GC2 double knockout prevented transport of rod PDE6, but not transducin, GRK1, or rhodopsin, to the rod outer segments. These knockout phenotypes suggest that PrBP/delta functions in extracting prenylated proteins from the endoplasmic reticulum (ER) where they dock after prenylation, and that GC-bearing membranes may co-transport peripheral membrane proteins in vesicles. We conclude that distinct pathways have evolved in rods and cones for transport of integral and peripherally membrane-associated proteins.
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PMID:A model for transport of membrane-associated phototransduction polypeptides in rod and cone photoreceptor inner segments. 1794 73

Proteins involved in the visual signaling cascade show light-dependent expression levels in photoreceptor cells. Recently, these proteins have been described to be expressed in neuroectodermal tumors and to function as cancer-retina antigens. Here, we show that light can down-regulate gene expression of rhodopsin, transducin, and cyclic guanosine 3',5'-monophosphate phosphodiesterase 6 (PDE6) and up-regulate guanylyl cyclase 1, recoverin, and arrestin in human melanoma cells in vitro, comparable to physiologic changes earlier observed in photoreceptor cells. Similar modulation can be detected at the protein level in melanoma cells except for no changes in PDE6 protein levels. Two regulatory pathways have been identified: Sp1/Sp3/Sp4 proteins for rhodopsin and PDE6, and mitogen-activated protein kinases for recoverin and arrestin. The visual cascade and retinoic acid as its derivate do not play any role in this process. Putative explanations for light-dependent modulation of cancer-retina antigen expression in melanoma cells are discussed.
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PMID:Visible light modulates the expression of cancer-retina antigens. 1818 73

Signal transduction in outer segments of vertebrate photoreceptors is mediated by a series of reactions among multiple polypeptides that form protein-protein complexes within or on the surface of the disk and plasma membranes. The individual components in the activation reactions include the photon receptor rhodopsin and the products of its absorption of light, the three subunits of the G protein, transducin, the four subunits of the cGMP phosphodiesterase, PDE6 and the four subunits of the cGMP-gated cation channel. Recovery involves membrane complexes with additional polypeptides including the Na(+)/Ca(2+), K(+) exchanger, NCKX2, rhodopsin kinases RK1 and RK7, arrestin, guanylate cyclases, guanylate cyclase activating proteins, GCAP1 and GCAP2, and the GTPase accelerating complex of RGS9-1, G(beta5L), and membrane anchor R9AP. Modes of membrane binding by these polypeptides include transmembrane helices, fatty acyl or isoprenyl modifications, polar interactions with lipid head groups, non-polar interactions of hydrophobic side chains with lipid hydrocarbon phase, and both polar and non-polar protein-protein interactions. In the course of signal transduction, complexes among these polypeptides form and dissociate, and undergo structural rearrangements that are coupled to their interactions with and catalysis of reactions by small molecules and ions, including guanine nucleotides, ATP, Ca(2+), Mg(2+), and lipids. The substantial progress that has been made in understanding the composition and function of these complexes is reviewed, along with the more preliminary state of our understanding of the structures of these complexes and the challenges and opportunities that present themselves for deepening our understanding of these complexes, and how they work together to convert a light signal into an electrical signal.
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PMID:Signal transducing membrane complexes of photoreceptor outer segments. 1845 4


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