Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.1.4.1 (phosphodiesterase)
18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cardiac myocytes incubated with 3-isobutyl-1-methylxanthine (IBMX), a nonspecific cyclic nucleotide phosphodiesterase inhibitor, formed rigor complexes under anoxic conditions more readily than cells incubated with other phosphodiesterase inhibitors. Cardiac myocytes were incubated for 1 hr with either (a) no additions, (b) 150 microM zaprinast, or (c) 1 mM IBMX, and then were rendered anoxic for periods up to 60 min. Cells were >80% viable throughout the anoxic period; viability was unaffected by either drug. Rod count decreased more rapidly after the onset of anoxia in the IBMX-treated cells than in control or zaprinast-treated cells (11% rods vs. roughly 47% rods after 30 min of anoxia). IBMX-treated cell groups also formed more "contracted" myocytes (box-like rods) than their untreated or zaprinast-treated counterparts (50% contracted vs. roughly 27% contracted after 30 min of anoxia). While nucleotide degradation patterns were similar in all experimental groups, the ratio of ATP to ADP was lower in IBMX-treated cells than in control or zaprinast-treated cells. The L-type calcium channel was apparently not involved in this phenomenon; while cyclic AMP was elevated in the IBMX-incubated cells, verapamil did not protect IBMX-incubated cells from premature damage by anoxia. Incubation with 8-cyclopentyl-1,3-dipropylxanthine (CDPX), an A1 receptor antagonist, at concentrations up to 1 microM in place of 1mM IBMX did not reproduce the IBMX effect. We concluded that IBMX sensitizes cardiac myocytes to anoxia through a mechanism related to its effect on ATP/ADP, and unrelated to an elevation of intracellular calcium or preconditioning phenomena.
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PMID:3-isobutyl-1-methylxanthine (IBMX) sensitizes cardiac myocytes to anoxia. 1209 83

cGMP-phosphodiesterase (PDE) is a key component in visual phototransduction. Rod and cone photoreceptors each produce their unique cGMP-PDE subunits. The alpha' catalytic subunits are believed to be cone-specific. In this study, we report that transfection of the -132 to +139 sequence in the upstream region of the human alpha'-PDE gene fused to luciferase cDNA gives the highest level of reporter gene transcription in cultured retinoblastoma Y79 cells. Transgenic Xenopus laevis carrying this sequence fused to green fluorescent protein (GFP) expressed GFP in cones, suggesting a conserved regulatory mechanism for alpha'-PDE transcription in both human and frog.
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PMID:Conserved transcriptional regulation of a cone phototransduction gene in vertebrates. 1552 96

Rod phosphodiesterase (PDE6) is the central effector enzyme in vertebrate visual transduction. Holo-PDE6 consists of two similar catalytic subunits (Palphabeta) and two identical inhibitory subunits (Pgamma). Palphabeta is the only heterodimer in the PDE superfamily, yet its significance for the function of PDE6 is poorly understood. An unequal interaction of Pgamma with Pbeta as compared with Palpha in the PDE6 complex has not been reported. We investigated the interaction interface between full-length Pgamma and Palphabeta, by differentiating Pgamma interaction with each individual Palphabeta subunit through radiolabel transfer from various positions throughout the entire Pgamma molecule. The efficiency of radiolabel transfer indicates that the close vicinity of serine 40 on Pgamma makes a major contribution to the interaction with Palphabeta. In addition, a striking asymmetry of interaction between the Pgamma polycationic region and the Palphabeta subunits was observed when the stoichiometry of Pgamma versus the Palphabeta dimer was below 2. Preferential photolabeling on Pbeta from Pgamma position 40 and on Palpha from position 30 increased while lowering the Pgamma/Palphabeta ratio, but diminished when the Pgamma/Palphabeta ratio was over 2. Our finding leads to the conclusion that two classes of Pgamma binding sites exist on Palphabeta, each composed of GAF domains in both Palpha and Pbeta, differing from the conventional models suggesting that each Pgamma binds only one of the Palphabeta catalytic subunits. This new model leads to insight into how the unique Palphabeta heterodimer contributes to the sophisticated regulation in visual transduction through interaction with Pgamma.
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PMID:Asymmetric interaction between rod cyclic GMP phosphodiesterase gamma subunits and alphabeta subunits. 1566 39

An absolute majority of cyclic nucleotide phosphodiesterases (PDEs) form catalytic dimers. The structural determinants and functional significance of PDE dimerization are poorly understood. Furthermore, all known dimeric PDEs with the exception of retinal rod guanosine 3',5'-cyclic-monophosphate PDE (PDE6) are homodimeric enzymes. Rod PDE6 is a catalytic heterodimer composed of alpha- and beta-subunits. Gel filtration, sucrose gradient centrifugation, and immunoprecipitation are standard techniques used to study dimerization of proteins. We successfully applied these methods to investigate dimerization of chimeric proteins between PDE6alphabeta and PDE5, which allowed us to elucidate the structural basis for heterodimerization of rod PDE6. This chapter outlines approaches to the investigation of PDE6 dimerization that can be utilized in a broader analysis of PDE dimerization.
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PMID:Analysis of dimerization determinants of PDE6 catalytic subunits. 1598 69

Rod responses to brief pulses of light were recorded as electroretinogram (ERG) mass potentials across isolated, aspartate-superfused rat retinas at different temperatures and intensities of steady background light. The objective was to clarify to what extent differences in sensitivity, response kinetics and light adaptation between mammalian and amphibian rods can be explained by temperature and outer-segment size without assuming functional differences in the phototransduction molecules. Corresponding information for amphibian rods from the literature was supplemented by new recordings from toad retina. All light intensities were expressed as photoisomerizations per rod (Rh*). In the rat retina, an estimated 34% of incident photons at the wavelength of peak sensitivity caused isomerizations in rods, as the (hexagonally packed) outer segments measured 1.7 microm x 22 microm and had specific absorbance of 0.016 microm(-1) on average. Fractional sensitivity (S) in darkness increased with cooling in a similar manner in rat and toad rods, but the rat function as a whole was displaced to a ca 0.7 log unit higher sensitivity level. This difference can be fully explained by the smaller dimensions of rat rod outer segments, since the same rate of phosphodiesterase (PDE) activation by activated rhodopsin will produce a faster drop in cGMP concentration, hence a larger response in rat than in toad. In the range 15-25 degrees C, the waveform and absolute time scale of dark-adapted dim-flash photoresponses at any given temperature were similar in rat and toad, although the overall temperature dependence of the time to peak (t(p)) was somewhat steeper in rat (Q(10) approximately 4 versus 2-3). Light adaptation was similar in rat and amphibian rods when measured at the same temperature. The mean background intensity that depressed S by 1 log unit at 12 degrees C was in the range 20-50 Rh* s(-1) in both, compared with ca 4500 Rh* s(-1) in rat rods at 36 degrees C. We conclude that it is not necessary to assume major differences in the functional properties of the phototransduction molecules to account for the differences in response properties of mammalian and amphibian rods.
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PMID:Light responses and light adaptation in rat retinal rods at different temperatures. 1603 91

Rod photoreceptors are activated by light through activation of a cascade that includes the G protein-coupled receptor rhodopsin, the G protein transducin, its effector cyclic guanosine monophosphate (cGMP) phosphodiesterase and the second messengers cGMP and Ca2+. Signalling is localised to the particular rod outer segment disc, which is activated by absorption of a single photon. Modelling of this cascade has previously been performed mostly by assumption of a well-stirred cytoplasm. We recently published the first fully spatially resolved model that captures the local nature of light activation. The model reduces the complex geometry of the cell to a simpler one using the mathematical theories of homogenisation and concentrated capacity. The model shows that, upon activation of a single rhodopsin, changes of the second messengers cGMP and Ca2+ are local about the particular activated disc. In the current work, the homogenised model is computationally compared with the full, non-homogenised one, set in the original geometry of the rod outer segment. It is found to have an accuracy of 0.03% compared with the full model in computing the integral response and a 5200-fold reduction in computation time. The model can reconstruct the radial time-profiles of cGMP and Ca2+ in the interdiscal spaces adjacent to the activated discs. Cellular electrical responses are localised near the activation sites, and multiple photons sufficiently far apart produce essentially independent responses. This leads to a computational analysis of the notion and estimate of 'spread' and the optimum distribution of activated sites that maximises the response. Biological insights arising from the spatio-temporal model include a quantification of how variability in the response to dim light is affected by the distance between the outer segment discs capturing photons. The model is thus a simulation tool for biologists to predict the effect of various factors influencing the timing, spread and control mechanisms of this G protein-coupled, receptor-mediated cascade. It permits ease of simulation experiments across a range of conditions, for example, clamping the concentration of calcium, with results matching analogous experimental results. In addition, the model accommodates differing geometries of rod outer segments from different vertebrate species. Thus it represents a building block towards a predictive model of visual transduction.
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PMID:Mathematical and computational modelling of spatio-temporal signalling in rod phototransduction. 1698 76

Photoreceptor degeneration is a common cause of inherited blindness worldwide. We have identified a blind zebrafish mutant with rapid degeneration of cone photoreceptors caused by a mutation in the cone phosphodiesterase c (pde6c) gene, a key regulatory component in cone phototransduction. Some rods also degenerate, primarily in areas with a low density of rods. Rod photoreceptors in areas of the retina that always have a high density of rods are protected from degeneration. Our findings demonstrate that, analogous to what happens to rod photoreceptors in the rd1 mouse model, loss of cone phosphodiesterase leads to rapid degeneration of cone photoreceptors. Furthermore, we propose that cell density plays a key role in determining whether rod photoreceptors degenerate as a secondary consequence to cone degeneration. Our zebrafish mutant serves as a model for developing therapeutic treatments for photoreceptor degeneration in humans.
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PMID:A mutation in the cone-specific pde6 gene causes rapid cone photoreceptor degeneration in zebrafish. 1807 98

Melatonin is involved in regulation of a variety of physiological functions through activation of specific G-protein coupled receptors. However, the neuromodulatory role of melatonin, released from photoreceptors in the retina, is poorly understood. Here we show that melatonin enhances the sensitivity of the rod signal pathway by potentiating signal transfer from rod photoreceptors to ON bipolar cells (Rod-ON-BCs). Whole-cell patch-clamp recordings showed that melatonin induced a sustained inward current from Rod-ON-BCs, through activation of the melatonin MT2 receptor, which was identified as one mediated by a cGMP-dependent cation channel. Consistent with this, melatonin was found, using immunocytochemistry, to increase intracellular cGMP levels, which was identified due to an inhibition of phosphodiesterase. Physiologically, melatonin potentiated responses of Rod-ON-BCs to simulated light flashes (brief puffs of CPPG, an mGluR6 antagonist, in the presence of l-AP4, an mGluR6 agonist), which was mediated by cGMP-dependent kinase, and increased the amplitude of the scotopic electroretinographic b-wave, a reflection of Rod-ON-BC activity. These results suggest that melatonin, being at a higher level at night, may improve the signal/noise ratio for rod signals in the outer retina by enhancing signal transfer from rods to BCs.
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PMID:Melatonin potentiates rod signals to ON type bipolar cells in fish retina. 1838 38

The present study describes a robust 50-fold increase in rhodopsin gene transcription by cAMP in cultured retinal precursor cells of chicken embryo. Retinal cells isolated at embryonic day 8 (E8) and cultured for 3 days in serum-supplemented medium differentiated mostly into red-sensitive cones and to a lesser degree into green-sensitive cones, as indicated by real-time RT-PCR quantification of each specific opsin mRNA. In contrast, both rhodopsin mRNA concentration and rhodopsin gene promoter activity required the presence of cAMP-increasing agents [forskolin and 3-isobutyl-1-methylxanthine (IBMX)] to reach significant levels. This response was rod-specific and was sufficient to activate rhodopsin gene transcription in serum-free medium. The increase in rhodopsin mRNA levels evoked by a series of cAMP analogs suggested the response was mediated by protein kinase A, not by EPAC. Membrane depolarization by high KCl concentration also increased rhodopsin mRNA levels and this response was strongly potentiated by IBMX. The rhodopsin gene response to cAMP-increasing agents was developmentally gated between E6 and E7. Rod-specific transducin alpha subunit mRNA levels also increased up to 50-fold in response to forskolin and IBMX, while rod-specific phosphodiesterase-VI and rod arrestin transcripts increased 3- to 10-fold. These results suggest a cAMP-mediated signaling pathway may play a role in rod differentiation.
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PMID:Cyclic AMP-dependent activation of rhodopsin gene transcription in cultured retinal precursor cells of chicken embryo. 1945 15

Leber congenital amaurosis (LCA) caused by mutations in Aryl hydrocarbon receptor interacting protein like-1 (Aipl1) is a severe form of childhood blindness. At 4 weeks of age, a mouse model of LCA lacking AIPL1 exhibits complete degeneration of both rod and cone photoreceptors. Rod cell death occurs due to rapid destabilization of rod phosphodiesterase, an enzyme essential for rod survival and function. However, little is understood regarding the role of AIPL1 in cone photoreceptors. Cone degeneration observed in the absence of AIPL1 could be due to an indirect 'bystander effect' caused by rod photoreceptor death or a direct role for AIPL1 in cones. To understand the importance of AIPL1 in cone photoreceptor cells, we transgenically expressed hAIPL1 exclusively in the rod photoreceptors of the Aipl1(-/-) mouse. Transgenic expression of hAIPL1 restored rod morphology and the rod-derived electroretinogram response, but cone photoreceptors were non-functional in the absence of AIPL1. In addition, the cone photoreceptors degenerate, but at a slower rate compared with Aipl1(-/-) mice. This degeneration is linked to the highly reduced levels of cone PDE6 observed in the hAIPL1 transgenic mice. Our studies demonstrate that AIPL1 is needed for the proper functioning and survival of cone photoreceptors. However, rod photoreceptors also provide support that partially preserves cone photoreceptors from rapid death in the absence of AIPL1.
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PMID:The Leber congenital amaurosis protein, AIPL1, is needed for the viability and functioning of cone photoreceptor cells. 2004 64


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