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)

The bovine retina rod cell protein with an apparent M(r) 26 kDa (p26 [1] or recoverin [2]) was suggested to be a calcium-sensitive regulator of photoreceptor guanylate cyclase. The data obtained show that highly purified p26 is not capable of restoring guanylate cyclase in washed ROS membranes up to the level of a ROS suspension. At the same time we found that a Ca(2+)-sensitive complex of p26 and a protein with apparent M(r) 67 kDa, presumably rhodopsin kinase, is present in the ROS extract. We suggest that rhodopsin kinase can be a functional target for p26 in retina rod cells.
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PMID:[Function of the calcium-binding protein p26 (recoverin) in bovine retinal rods]. 791 52

Tyrphostins are a group of organic compounds which are widely used as a tool to specifically inhibit protein tyrosine kinases (Yaish, P., Gazit, A., Gilon, C., and levitzki A. (1988) Science 242, 933-935; Gazit, A., Yaish, P., Gilon, C., and Levitzki A. (1989) J. Med. Chem. 32, 2344-2352; Lyall, R. M., Zilberstein, A., Gazit, A., Gilon, C., Levitzki, A., and Schlessinger J. (1989) J. Biol. Chem. 264, 14503-14509; Osherov, N., Gazit, A., Gilon, C., and Levitzki, A. (1993) J. Biol. Chem. 268, 11134-11142). We report here that members of the tyrphostin family inhibit the GTPase activity of transducin and the enzymatic activities of other GTP-utilizing proteins in retinal rod outer segments, such as guanylyl cyclase or fructose-6-phosphate kinase. In contrast, ATP-utilizing enzymes such as hexokinase or rhodopsin kinase were not effected.
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PMID:Inhibition of GTP-utilizing enzymes by tyrphostins. 791 15

A decrease of cytoplasmic Ca(2+)-concentration in vertebrate photoreceptor cells after illumination is necessary for light adaptation. Although the mechanisms of adaptation is not completely understood, several Ca(2+)-dependent cellular processes have been discovered. Some involve calcium-binding proteins like recoverin, guanylyl cyclase-activating protein and calmodulin, and their target proteins rhodopsin kinase, guanylyl cyclase, the cGMP-gated channel, and NO synthase. The activity of several enzymes or channels is directly controlled by Ca2+ and does not involve calcium-binding proteins. These proteins are pyrophosphatase, protein kinase C and the cGMP-gated channel.
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PMID:Control of photoreceptor proteins by Ca2+. 855 70

Neurocalcins belong to a family of neuronal specific EF hand Ca2+-binding proteins defined by recoverin. Previously, we reported the cloning and initial characterization of neurocalcin in Drosophila melanogaster (Teng, D. H.-F., Chen, C.-K., and Hurley, J. B. (1994) J. Biol. Chem. 269, 31900-31907). We showed that the Drosophila neurocalcin protein (DrosNCa) is expressed in neurons and that bacterially expressed recombinant DrosNCa (rDrosNCa) can be myristoylated. Here, we present two lines of evidence that DrosNCa is fatty acylated in vivo. First, the mobility of affinity-purified native DrosNCa on two-dimensional gel electrophoresis is identical to that of myristoylated rDrosNCa and distinct from that of nonacylated rDrosNCa. Second, the membrane binding properties of native DrosNCa are similar to those of myristoylated rDrosNCa; both of these proteins bind to membranes at 0.2 mM Ca2+, whereas nonacylated rDrosNCa always remains soluble. It has been shown that recoverin inhibits the phosphorylation of rhodopsin when Ca2+ is present (Kawamura et al., 1993) and that a dependent recoverin/rhodopsin kinase interaction underlies the inhibitory effect of recoverin (Chen et al., 1995). Given the similarities between recoverin and neurocalcin, we examined the effect of DrosNCa on rhodopsin phosphorylation. We find that rDrosNCa is capable of inhibiting bovine rhodopsin phosphorylation in vitro in a Ca2+-dependent manner. The inhibitory activity of rDrosNCa is enhanced by myristoylation, and the potency of its effect is similar to that of recoverin. Two other related EF hand proteins, guanylate cyclase-activating protein-2 and calmodulin, are only poor inhibitors in these phosphorylation assays. in vitro inhibition of rhodopsin phosphorylation therefore appears to be an assayable property of a subset of recoverin-like proteins.
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PMID:Drosophila neurocalcin, a fatty acylated, Ca2+-binding protein that associates with membranes and inhibits in vitro phosphorylation of bovine rhodopsin. 862 92

A rich variety of mechanisms govern the inactivation of the rod phototransduction cascade. These include rhodopsin phosphorylation and subsequent binding of arrestin; modulation of rhodopsin kinase by S-modulin (recoverin); regulation of G-protein and phosphodiesterase inactivation by GTPase-activating factors; and modulation of guanylyl cyclase by a high-affinity Ca(2+)-binding protein. The dependence of several of the inactivation mechanisms on Ca2+i makes it difficult to assess the contributions of these mechanisms to the recovery kinetics in situ, where Ca2+i is dynamically modulated during the photoresponse. We recorded the circulating currents of salamander rods, the inner segments of which are held in suction electrodes in Ringer's solution. We characterized the response kinetics to flashes under two conditions: when the outer segments are in Ringer's solution, and when they are in low-Ca2+ choline solutions, which we show clamp Ca2+i very near its resting level. At T = 20-22 degrees C, the recovery phases of responses to saturating flashes producing 10(2.5)-10(4.5) photoisomerizations under both conditions are characterized by a dominant time constant, tau c = 2.4 +/- 0.4 s, the value of which is not dependent on the solution bathing the outer segment and therefore not dependent on Ca2+i. We extended a successful model of activation by incorporating into it a first-order inactivation of R*, and a first-order, simultaneous inactivation of G-protein (G*) and phosphodiesterase (PDE*). We demonstrated that the inactivation kinetics of families of responses obtained with Ca2+i clamped to rest are well characterized by this model, having one of the two inactivation time constants (tau r* or tau PDE*) equal to tau c, and the other time constant equal to 0.4 +/- 0.06 s.
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PMID:The kinetics of inactivation of the rod phototransduction cascade with constant Ca2+i. 874 28

The photoreceptor membrane guanylate cyclase is a member of a family of proteins with a set of four structural motifs: an extracellular ligand binding domain, a transmembrane domain, an intracellular protein kinase-like domain, and an intracellular catalytic domain. Purified preparations of the photoreceptor guanylate cyclase have allowed us to explore the function of the protein kinase-like domain. ATP enhances the guanylate cyclase activity 2-fold in membranes stripped of peripheral proteins. The stimulation can be mimicked by ATPgammaS (adenosine 5'-O-(3-thiotriphosphate)), AMPPNP (5'-adenylyl beta,gamma-imidodiphosphate), and ADP, but not AMP. While this effect is lost by solubilizing guanylate cyclase, ATP binds the purified, solubilized enzyme in a site distinct from the catalytic GTP site as shown by specific labeling with 8-N3[alpha-32P]ATP. The enzyme has a protein kinase activity that is Mg2+-dependent and autophosphorylates serine residues. Myelin basic protein serves as a substrate for the kinase and enables further characterization of the kinase properties. The Km for ATP is 81 microM. The kinase activity is unaffected by calcium, cyclic nucleotides, and phorbol 12-myristate 13-acetate/L-alpha-phosphatidylserine/Ca2+ and is inhibited by high concentrations of staurosporine. These properties are distinct from other Ser/Thr kinases identified in rod outer segment preparations including protein kinase A, protein kinase C, and rhodopsin kinase. The observations offer the first biochemical evidence that a member of the receptor guanylate cyclase family has intrinsic protein kinase activity.
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PMID:The photoreceptor guanylate cyclase is an autophosphorylating protein kinase. 890 Jan 99

When light is absorbed within the outer segment of a vertebrate photoreceptor, the conformation of the photopigment rhodopsin is altered to produce an activated photoproduct called metarhodopsin II or Rh(*). Rh(*) initiates a transduction cascade similar to that for metabotropic synaptic receptors and many hormones; the Rh(*) activates a heterotrimeric G protein, which in turn stimulates an effector enzyme, a cyclic nucleotide phosphodiesterase. The phosphodiesterase then hydrolyzes cGMP, and the decrease in the concentration of free cGMP reduces the probability of opening of channels in the outer segment plasma membrane, producing the electrical response of the cell. Photoreceptor transduction can be modulated by changes in the mean light level. This process, called light adaptation (or background adaptation), maintains the working range of the transduction cascade within a physiologically useful region of light intensities. There is increasing evidence that the second messenger responsible for the modulation of the transduction cascade during background adaptation is primarily, if not exclusively, Ca(2+), whose intracellular free concentration is decreased by illumination. The change in free Ca(2+) is believed to have a variety of effects on the transduction mechanism, including modulation of the rate of the guanylyl cyclase and rhodopsin kinase, alteration of the gain of the transduction cascade, and regulation of the affinity of the outer segment channels for cGMP. The sensitivity of the photoreceptor is also reduced by previous exposure to light bright enough to bleach a substantial fraction of the photopigment in the outer segment. This form of desensitization, called bleaching adaptation (the recovery from which is known as dark adaptation), seems largely to be due to an activation of the transduction cascade by some form of bleached pigment. The bleached pigment appears to activate the G protein transducin directly, although with a gain less than Rh(*). The resulting decrease in intracellular Ca(2+) then modulates the transduction cascade, by a mechanism very similar to the one responsible for altering sensitivity during background adaptation.
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PMID:Adaptation in vertebrate photoreceptors. 1115 56

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

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

Lecithin retinol acyl transferase (LRAT) and retinal pigment epithelium protein 65 (RPE65) are key enzymes of the retinoid cycle. In Lrat(-/-) and Rpe65(-/-) mice, models of human Leber congenital amaurosis, the retinoid cycle is disrupted and 11-cis-retinal, the chromophore of visual pigments, is not produced. The Lrat(-/-) and Rpe65(-/-) retina phenotype presents with rapid sectorial cone degeneration, and the visual pigments, S-opsin and M/L-opsin, fail to traffic to cone outer segments appropriately. In contrast, rod opsin traffics normally in mutant rods. Concomitantly, guanylate cyclase 1, cone T alpha-subunit, cone phosphodiesterase 6alpha' (PDE6alpha'), and GRK1 (G-protein-coupled receptor kinase 1; opsin kinase) are not transported to Lrat(-/-) and Rpe65(-/-) cone outer segments. Aberrant localization of these membrane-associated proteins was evident at postnatal day 15, before the onset of ventral and central cone degeneration. Protein levels of cone T alpha and cone PDE6alpha' were reduced, whereas their transcript levels were unchanged, suggesting posttranslational degradation. In an Rpe65(-/-)Rho(-/-) double knock-out model, trafficking of cone pigments and membrane-associated cone phototransduction polypeptides to the outer segments proceeded normally after 11-cis-retinal administration. These results suggest that ventral and central cone opsins must be regenerated with 11-cis-retinal to permit transport to the outer segments. Furthermore, the presence of 11-cis-retinal is essential for proper transport of several membrane-associated cone phototransduction polypeptides in these cones.
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PMID:Trafficking of membrane-associated proteins to cone photoreceptor outer segments requires the chromophore 11-cis-retinal. 1840 Sep


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