Retinal phosphodiesterase 6 (PDE6) (PDE6)

Retinal phosphodiesterase 6 (PDE6) is the central effector enzyme in the vertebrate visual phototransduction cascade, primarily located in the outer segments of rod and cone photoreceptor cells (Cote, 2004). The nonactivated PDE6 holoenzyme exists as a complex where catalytic subunits (alpha and beta in rods, or a homodimer of alpha-prime in cones) are kept in an inactive state by the tight binding of inhibitory gamma subunits (Zhang et al., 2015). Upon light activation, the alpha subunit of the G-protein transducin (Gt-alpha) binds to the gamma subunits, sequestering them and allowing the catalytic core to rapidly hydrolyze cyclic guanosine monophosphate (cGMP) (UniProt P16499). This rapid depletion of cGMP leads to the closure of cyclic nucleotide-gated (CNG) ion channels, resulting in membrane hyperpolarization and the transmission of visual signals to the brain (NCBI Gene 5145). Mutations in the subunits of PDE6 are linked to various forms of inherited retinal blindness, including retinitis pigmentosa and achromatopsia (PubMed 25649234). Furthermore, PDE6 is a notable off-target for PDE5 inhibitors like sildenafil, which can lead to transient visual disturbances such as cyanopsia due to the structural similarity between the catalytic domains of PDE5 and PDE6 (PubChem CID 5212).

Other names

cGMP-specific 3',5'-cyclic phosphodiesterase 6Rod-specific cGMP phosphodiesteraseCone-specific cGMP phosphodiesterasePDE6 holoenzymeNonactivated PDE6 holoenzyme

Inhibition of cGMP hydrolysis by competitive binding to the catalytic site of the alpha and beta subunits (Cote, 2004).