The photoreceptor phosphodiesterase (PDE6) is a member of large family of Class I phosphodiesterases responsible for hydrolyzing the second messengers cAMP and cGMP. PDE6 consists of two catalytic subunits and two inhibitory subunits that form a tetrameric protein. PDE6 is a peripheral membrane protein that is localized to the signaling-transducing compartment of rod and cone photoreceptors. As the central effector enzyme of the G-protein coupled visual transduction pathway, activation of PDE6 catalysis causes in a rapid decrease in cGMP levels that results in closure of cGMP-gated ion channels in the photoreceptor plasma membrane. Because of its importance in the phototransduction pathway, mutations in PDE6 genes result in various retinal diseases that currently lack therapeutic treatment strategies due to inadequate knowledge of the structure, function, and regulation of this enzyme. This review focuses on recent progress in understanding the structure of the regulatory and catalytic domains of the PDE6 holoenzyme, the central role of the multi-functional inhibitory γ-subunit, the mechanism of activation by the heterotrimeric G protein, transducin, and future directions for pharmacological interventions to treat retinal degenerative diseases arising from mutations in the PDE6 genes.
Molecular, Cellular and Biomedical Sciences
Grant/Award Number and Agency
National Eye Institute (NIH), R01 EY05798); National Institute of General Medical Sciences (NIH), P20 GM113131
Adv Exp Med Biol. Protein Reviews
Digital Object Identifier (DOI)
Cote, Rick H.; Gupta, Richa; Irwin, Michael J.; and Wang, Xin, "Photoreceptor phosphodiesterase (PDE6): structure, regulatory mechanisms, and implications for treatment of retinal diseases" (2021). Adv Exp Med Biol. Protein Reviews. 1236.