Function and regulation of photoreceptor phosphodiesterase (PDE6) in the visual signaling pathway.



This chapter focuses on the catalytic and regulatory features of the photoreceptor phosphodiesterase 6 (PDE6) that make it suitable as the central effector of the visual transduction pathway. Photoreceptor PDE6 is one of the 11 PDE family members that comprise the class I cyclic nucleotide PDE superfamily. These enzymes regulate the cellular levels of cAMP and/or cGMP. Some PDE families are specific for one cyclic nucleotide, while others are dual substrate enzymes. All class I PDEs possess a conserved catalytic region of approximately 270 amino acids located toward the C-terminus of the primary sequence. Most PDE families contain a regulatory region located within their N-terminal region. The primary sequences of the catalytic subunits of rod PDE6 are coded by two distinct genes, β (gene name, PDE6A) and β (gene name, PDE6B), which form a catalytic heterodimer, β α. A PDE6 catalytic subunit consists of highly conserved regulatory GAF domains, a catalytic domain, and a C-terminus that is posttranslationally modified. There are no X-ray crystal structures available for PDE6 holoenzyme or for individual catalytic or regulatory domains of the protein. The catalytic domain of PDE6 is likely to consist of 16 α-helices arranged into three subdomains. Two metal ions such as zinc and magnesium are coordinated by a group of 6 invariant residues present in all 11 class I PDE families, and form an integral part of the active site of PDE6. The ability of light-activated PDE6 to hydrolyze cGMP at the diffusion-controlled limit is essential for light-induced changes in cGMP levels to occur on the millisecond timescale needed for the physiological response of rods and cones to illumination.


Molecular, Cellular and Biomedical Sciences

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