Regulation of retinal cgmp phosphodiesterases

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Project Title: Regulation of retinal cgmp phosphodiesterases
Principal Investigators (PI): ARTEMYEV NIKOLAI O
Project Number: 2R01EY010843-15A1
Organization: UNIVERSITY OF IOWA
 
Project Description:
[unreadable] (provided by applicant): The long-term goal of this research program is to elucidate the molecular mechanisms of the function and regulation of rod and cone cGMP-phosphodiesterases (PDE6). PDE6s serve as key effector enzymes in the vertebrate visual transduction cascade. Transducin activates PDE6 by relieving the inhibition imposed on the PDE6 catalytic dimer by two ?-subunits (P3). Rod PDE6 is unique among cyclic nucleotide PDEs in that it is a catalytic heterodimer composed of the PDE6A and PDE6B catalytic subunitsWe hypothesize that the heterodimerization of rod PDE6 plays an important role in rod phototransduction. The individual properties of PDE6A and PDE6B and the functional significance of rod PDE6 heterodimerization will be examined in aim 1. The goal is to bring a new level of understanding to the mechanism of rod PDE6 activation by transducin and advance the current models of the rod phototransduction cascade. Based on the existing evidence and our preliminary studies, we hypothesize that the interaction of P? with the PDE6 catalytic subunits is critical to the proper transport of the holoenzyme in photoreceptor cells. Aim 2 is to test this hypothesis and probe the mechanisms of P? in expression and transport of PDE6. Aims 1 and 2 will be achieved through extensive use of transgenic Xenopus laevis as a novel approach for the expression of mutant PDE6. Mutations in the human PDE6A and PDE6B genes each are responsible for 3-4% of cases of recessive retinitis pigmentosa (RP). As aim 3 we will investigate the mechanism of the recessive mutation N605S in the mouse PDE6B subunit causing atypical retinal degeneration (atrd3) in mice. Based on the initial evidence, we hypothesize that atrd3 is triggered by functional changes in PDE6 and may reflect certain forms and mechanisms of human RP. The atrd3 mechanism will be examined using the mutant mouse model in comparison to a transgenic Xenopus laevis model of the cone PDE6C mutant counterpart. The molecular details of PDE6 inhibition by its ?-subunit will be elucidated by means of protein crystallography in aim 4. The structure of the chimeric PDE5/6 catalytic domain complexed with P?-63-87 and sildenafil (Viagra) will provide the first structural insights into the critical interaction between PDE6 and P? and should reveal the structural basis for the side effects of Viagra on vision. The structure of the chimeric atrd3 mutant will be investigated to uncover the molecular mechanism for retinal disease associated with this PDE6 mutation. Overall, these studies will advance our understanding of the regulation of PDE6 and help to elucidate the mechanisms of RP caused by mutations of PDE6 genes. PUBLIC HEALTH RELEVANCE: Rod and cone cGMP phosphodiesterases (PDE6 family) are the key effector enzymes in vision. Mutations in PDE6 lead to human retinal diseases such as retinitis pigmentosa, congenital stationary night blindness, and achromatopsia. This research would develop a new level of understanding of structure, function, and regulation of PDE6 necessary to uncover the mechanisms of PDE6 mutations in diseased retina. [unreadable] [unreadable] [unreadable]
 
Project Terms:
Abbott brand of sildenafil citrate Adverse effects Animal Model Animal Models and Related Studies Auricle Helix Binding Sites Biochemical C-terminal Catalytic Core Catalytic Domain Catalytic Region Catalytic Site Catalytic Subunit Combining Site Complex Cone Cones (Eye) Cones (Retina) Coupled Crystallographies Crystallography Crystallography, X-Ray Crystallography, X-Ray Diffraction Crystallography, X-Ray/Neutron Crystallography, Xray Cyclic GMP Cyclic Nucleotides Enzymes Family Fluorescence Frog G-Protein, Inhibitory Gt Genes Genetic Alteration Genetic Change Genetic defect Goals Gt, Transducin G-Protein Guanosine Cyclic 3',5'-Monophosphate Guanosine Cyclic Monophosphate Guanosine, cyclic 3',5'-(hydrogen phosphate) Helix Helix (Snails) Helix of ear Heterodimerization Holoenzymes Human Human, General Hydrolysis Individual Lead Leber's disease Life Link Mammals, Mice Man (Taxonomy) Man, Modern Mice Mice, Mutant Strains Modeling Models, Structural Molecular Monitor Murine Mus Mutagenesis, Site-Directed Mutant Strains Mice Mutation Night Blindness Nucleotides, Cyclic Nyctalopia PDE Pb element Pfizer brand of sildenafil citrate Phosphodiesterases Photoreceptor Cell Photoreceptors Photoreceptors, Cone Photoreceptors, Vertebrate Photosensitive Cell Phototransduction Pigmentary Retinopathy Platanna Play Programs (PT) Programs [Publication Type] Property Property, LOINC Axis 2 Proteins Public Health Rana Rana (genus) Reactive Site Regulation Research Retina Retinal Retinal Cone Retinal Degeneration Retinal Diseases Retinal Disorder Retinitis Pigmentosa Rod Rod Photoreceptors Rod-Cone Dystrophy Rods (Eye) Rods (Retina) Rods and Cones Role Sight Signal Transduction, Light Single Crystal Diffraction Site-Directed Mutagenesis Site-Specific Mutagenesis Solutions Structural Models Structure Structure-Activity Relationship Tapetoretinal Degeneration Targeted DNA Modification Targeted Modification Testing Transducin Transgenic Organisms Treatment Side Effects Vertebrate Photoreceptors Viagra Vision Visual Receptor Visual Transduction X Ray Crystallographies X-Ray Crystallography Xenopus Xenopus laevis achromatopsia base cGMP chemical structure function cone cell dimer ear helix experiment experimental research experimental study gene product genome mutation guanosine 3'5'monophosphate heavy metal Pb heavy metal lead insight model organism mouse mutant mutant mutant mouse model new approaches novel approaches novel strategies novel strategy peptide P peptide P glycosylase phosphoric diester hydrolase programs public health medicine (field) research study retina degeneration retina disease retina disorder retinal degenerative retinopathy rod cell side effect sildenafil social role structure function relationship therapy adverse effect transgenic treatment adverse effect
Project Title: Regulation of retinal cgmp phosphodiesterases
Principal Investigators (PI): ARTEMYEV NIKOLAI O
Project Number: 2R01EY010843-15A1
Organization: UNIVERSITY OF IOWA
 
Project Categories:
• Natural Sciences > Aging Diseases and Pathology, Aging-related markers and targets > Neurodegenerative diseases, Biomarkers of diseases > Visual disorders biomarkers
 
Other Information:
Fiscal Year: 1995
Project Start Date: 1 January 1994
Project End Date: 28 February 2013
Administering Institute Or Center: EY
 
Project Funding Information:
Total Funding: $371,090
Year Funding Organization Total Funding, $
2008 NATIONAL EYE INSTITUTE $371,090
Project Title: Regulation of retinal cgmp phosphodiesterases
Principal Investigators (PI): ARTEMYEV NIKOLAI O
Project Number: 2R01EY010843-15A1
Organization: UNIVERSITY OF IOWA
 
Project_number Title Year FY Total Cost
There are no results for this project in database.
Project Title: Regulation of retinal cgmp phosphodiesterases
Principal Investigators (PI): ARTEMYEV NIKOLAI O
Project Number: 2R01EY010843-15A1
Organization: UNIVERSITY OF IOWA
 
Project number Project title Organization FY Funding Organization FY Total Cost
2R01EY012682-05Molecular Mechanism of Photoreceptor G Protein SignalingUNIVERSITY OF IOWA2004NATIONAL EYE INSTITUTE
$368,750
5R01EY010843-11Regulation of Retinal cGMP PhosphodiesterasesUNIVERSITY OF IOWA2004NATIONAL EYE INSTITUTE
$331,875
5R01EY012682-04MOLECULAR MECHANISM OF PHOTORECEPTOR G PROTEIN SIGNALINGUNIVERSITY OF IOWA2003NATIONAL EYE INSTITUTE
$220,500
2R01EY010843-10Regulation of Retinal cGMP PhosphodiesterasesUNIVERSITY OF IOWA2003NATIONAL EYE INSTITUTE
$331,313
5R01EY012682-03MOLECULAR MECHANISM OF PHOTORECEPTOR G PROTEIN SIGNALINGUNIVERSITY OF IOWA2002NATIONAL EYE INSTITUTE
$220,500
5R01EY010843-09REGULATION OF RETINAL CYCLIC GMP PHOSPHODIESTERASESUNIVERSITY OF IOWA2002NATIONAL EYE INSTITUTE
$223,231
5R01EY012682-02MOLECULAR MECHANISM OF PHOTORECEPTOR G PROTEIN SIGNALINGUNIVERSITY OF IOWA2001NATIONAL EYE INSTITUTE
$220,500
5R01EY010843-08REGULATION OF RETINAL CYCLIC GMP PHOSPHODIESTERASESUNIVERSITY OF IOWA2001NATIONAL EYE INSTITUTE
$216,729
1R01EY012682-01A1MOLECULAR MECHANISM OF PHOTORECEPTOR G PROTEIN SIGNALINGUNIVERSITY OF IOWA2000NATIONAL EYE INSTITUTE
$217,351
5R01EY010843-07REGULATION OF RETINAL CYCLIC GMP PHOSPHODIESTERASESUNIVERSITY OF IOWA2000NATIONAL EYE INSTITUTE
$210,416
5R01EY010843-12Regulation of Retinal cGMP PhosphodiesterasesUNIVERSITY OF IOWA2005NATIONAL EYE INSTITUTE
$331,875
5R01EY012682-06Molecular Mechanism of Photoreceptor G Protein SignalingUNIVERSITY OF IOWA2005NATIONAL EYE INSTITUTE
$368,750
5R01EY010843-13Regulation of Retinal cGMP PhosphodiesterasesUNIVERSITY OF IOWA2006NATIONAL EYE INSTITUTE
$324,077
5R01EY012682-07Molecular Mechanism of Photoreceptor G Protein SignalingUNIVERSITY OF IOWA2006NATIONAL EYE INSTITUTE
$360,084
5R01EY010843-14Regulation of Retinal cGMP PhosphodiesterasesUNIVERSITY OF IOWA2007NATIONAL EYE INSTITUTE
$322,262
5R01EY012682-08Molecular Mechanism of Photoreceptor G Protein SignalingUNIVERSITY OF IOWA2007NATIONAL EYE INSTITUTE
$358,068
2R01EY010843-15A1Regulation of Retinal cGMP phosphodiesterasesUNIVERSITY OF IOWA2008NATIONAL EYE INSTITUTE
$371,090
5R01EY012682-09Molecular Mechanism of Photoreceptor G Protein SignalingUNIVERSITY OF IOWA2008NATIONAL EYE INSTITUTE
$350,907
5R01EY010843-16Regulation of Retinal cGMP phosphodiesterasesUNIVERSITY OF IOWA2009NATIONAL EYE INSTITUTE
$370,972
3R01EY010843-16S1Regulation of Retinal cGMP phosphodiesterasesUNIVERSITY OF IOWA2009NATIONAL EYE INSTITUTE
$54,082
Project Title: Regulation of retinal cgmp phosphodiesterases
Principal Investigators (PI): ARTEMYEV NIKOLAI O
Project Number: 2R01EY010843-15A1
Organization: UNIVERSITY OF IOWA
 
Project number Project title Principal investigator
There are no any related projects.
Project Title: Regulation of retinal cgmp phosphodiesterases
Principal Investigators (PI): ARTEMYEV NIKOLAI O
Project Number: 2R01EY010843-15A1
Organization: UNIVERSITY OF IOWA
 
Title Abstract Authors Year Rel
Intrinsically disordered gamma-subunit of cGMP phosphodiesterase encodes functionally relevant transient secondary and tertiary structure. Proceedings of the National Academy of Sciences of the United States of America. 2008 Feb 5 105 (5) :1505-10 Song, Jikui; Guo, Lian-Wang; Muradov, Hakim; Artemyev, Nikolai O; Ruoho, Arnold E; Markley, John L 2008