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.
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.
|Gopalakrishna, Kota N; Boyd, Kimberly; Yadav, Ravi P et al. (2016) Aryl Hydrocarbon Receptor-interacting Protein-like 1 Is an Obligate Chaperone of Phosphodiesterase 6 and Is Assisted by the Î³-Subunit of Its Client. J Biol Chem 291:16282-91|
|Cheguru, Pallavi; Majumder, Anurima; Artemyev, Nikolai O (2015) Distinct patterns of compartmentalization and proteolytic stability of PDE6C mutants linked to achromatopsia. Mol Cell Neurosci 64:1-8|
|Majumder, Anurima; Pahlberg, Johan; Muradov, Hakim et al. (2015) Exchange of Cone for Rod Phosphodiesterase 6 Catalytic Subunits in Rod Photoreceptors Mimics in Part Features of Light Adaptation. J Neurosci 35:9225-35|
|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|
|Manes, GaÃ«l; Cheguru, Pallavi; Majumder, Anurima et al. (2014) A truncated form of rod photoreceptor PDE6 Î²-subunit causes autosomal dominant congenital stationary night blindness by interfering with the inhibitory activity of the Î³-subunit. PLoS One 9:e95768|
|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|
|Grau, Tanja; Artemyev, Nikolai O; Rosenberg, Thomas et al. (2011) Decreased catalytic activity and altered activation properties of PDE6C mutants associated with autosomal recessive achromatopsia. Hum Mol Genet 20:719-30|
|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|
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