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 effectors enzymes in the vertebrate visual transduction cascade. The phototransduction cascades in rods and cones are principally similar, and the main rod and cone signaling molecules are highly homologous. In contrast, the physiology of rods and cones is markedly dissimilar, most notably with respect to sensitivity, response kinetics, and adaptation range. These differences are fundamental to the ability of the dual photoreceptor visual system to operate within a wide range of light intensities, yet they are poorly understood. Elucidating the molecular origins of the differences in physiology of rods and cones is a major current task in the phototransduction field. We hypothesize that distinct rod and cone PDE6 provide an important contribution into dissimilar physiology of rods and cones. The first main goal of the proposed research is to test this hypothesis with the use of a novel and robust transgenic mouse model expressing cone PDE6C instead of functional PDEAB in rods. These studies will establish the significance of different PDE6 isozymes in rods and cones. Furthermore, we expect to significantly advance understanding of cone PDE6 signaling, which at present is underdeveloped. The second major focus of this proposal is the study of PDE6 transport in photoreceptor cells and mistrafficking of PDE6 mutants as a mechanism of PDE6-linked retinal diseases. Mutations in PDE6 are known to cause retinitis pigmentosa (RP) and achromatopsia in humans. We hypothesize that PDE6 mistrafficking is a primary underlying mechanism of certain missense PDE6 mutations associated with the retinal diseases. The structural requirements for proper transport of PDE6, the mechanisms of mutant PDE6 enzymes, and their trafficking in photoreceptor cells will be examined using transgenic X. laevis. The ultimate goal is to generate important insights into the mechanisms of PDE6-linked RP and achromatopsia that will impact development of therapeutical interventions for these retinal dysfunctions.

Public Health Relevance

Rod and cone cGMP phosphodiesterases (PDE6 family) are the key effector enzymes in vision. Mutations in rod and cone PDE6 lead to human retinal diseases, such as retinitis pigmentosa and achromatopsia. The goals are to elucidate the differences between rod and cone PDE6 in relation to the distinct physiology of rods and cones and to achieve a new level of understanding of the mechanisms of PDE6 mutations in diseased retina. Mechanistic insights are sought that may aid development of therapeutical interventions for the PDE6-linked diseases.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01EY010843-21
Application #
8712489
Study Section
(BVS)
Program Officer
Neuhold, Lisa
Project Start
Project End
Budget Start
Budget End
Support Year
21
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Iowa
Department
Physiology
Type
Schools of Medicine
DUNS #
City
Iowa City
State
IA
Country
United States
Zip Code
52242
Cheguru, Pallavi; Majumder, Anurima; Artemyev, Nikolai O (2015) Distinct patterns of compartmentalization and proteolytic stability of PDE6C mutants linked to achromatopsia. Mol Cell Neurosci 64:8-Jan
Manes, Gaƫl; Cheguru, Pallavi; Majumder, Anurima et al. (2014) A truncated form of rod photoreceptor PDE6 ?-subunit causes autosomal dominant congenital stationary night blindness by interfering with the inhibitory activity of the ?-subunit. PLoS One 9:e95768
Cheguru, Pallavi; Zhang, Zhongming; Artemyev, Nikolai O (2014) The GAFa domain of phosphodiesterase-6 contains a rod outer segment localization signal. J Neurochem 129:256-63
Majumder, Anurima; Gopalakrishna, Kota N; Cheguru, Pallavi et al. (2013) Interaction of aryl hydrocarbon receptor-interacting protein-like 1 with the farnesyl moiety. J Biol Chem 288:21320-8
Muradov, Hakim; Boyd, Kimberly K; Kerov, Vasily et al. (2012) Atypical retinal degeneration 3 in mice is caused by defective PDE6B pre-mRNA splicing. Vision Res 57:1-8
Muradov, Hakim; Boyd, Kimberly K; Artemyev, Nikolai O (2010) Rod phosphodiesterase-6 PDE6A and PDE6B subunits are enzymatically equivalent. J Biol Chem 285:39828-34
Zhang, Zhongming; Artemyev, Nikolai O (2010) Determinants for phosphodiesterase 6 inhibition by its gamma-subunit. Biochemistry 49:3862-7
Muradov, Hakim; Boyd, Kimberly K; Haeri, Mohammad et al. (2009) Characterization of human cone phosphodiesterase-6 ectopically expressed in Xenopus laevis rods. J Biol Chem 284:32662-9
Barren, Brandy; Gakhar, Lokesh; Muradov, Hakim et al. (2009) Structural basis of phosphodiesterase 6 inhibition by the C-terminal region of the gamma-subunit. EMBO J 28:3613-22
Song, Jikui; Guo, Lian-Wang; Muradov, Hakim et al. (2008) Intrinsically disordered gamma-subunit of cGMP phosphodiesterase encodes functionally relevant transient secondary and tertiary structure. Proc Natl Acad Sci U S A 105:1505-10

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