title: Cone phosphodiesterase-6α' restores rod function and confers distinct physiological properties in the rod phosphodiesterase-6β-deficient rd10 mouse.
abstract: Phosphodiesterase-6 (PDE6) is the key effector enzyme of the vertebrate phototransduction pathway in rods and cones. Rod PDE6 catalytic core is composed of two distinct subunits, PDE6α and PDE6β, whereas two identical PDE6α' subunits form the cone PDE6 catalytic core. It is not known whether this difference in PDE6 catalytic subunit identity contributes to the functional differences between rods and cones. To address this question, we expressed cone PDE6α' in the photoreceptor cells of the retinal degeneration 10 (rd10) mouse that carries a mutation in rod PDEβ subunit. We show that adeno-associated virus-mediated subretinal delivery of PDE6α' rescues rod electroretinogram responses and preserves retinal structure, indicating that cone PDE6α' can couple effectively to the rod phototransduction pathway. We also show that restoration of light sensitivity in rd10 rods is attributable to assembly of PDE6α' with rod PDE6γ. Single-cell recordings revealed that, surprisingly, rods expressing cone PDE6α' are twofold more sensitive to light than wild-type rods, most likely because of the slower shutoff of their light responses. Unlike in wild-type rods, the response kinetics in PDE6α'-treated rd10 rods accelerated with increasing flash intensity, indicating a possible direct feedback modulation of cone PDE6α' activity. Together, these results demonstrate that cone PDE6α' can functionally substitute for rod PDEαβ in vivo, conferring treated rods with distinct physiological properties.
authors.affiliation: Department of Ophthalmology, University of Florida, Gainesville, Florida 32610, USA. wdeng@ufl.edu
authors.forename: Wen-Tao
authors.initials: WT
authors.lastname: Deng
authors.forename: Keisuke
authors.initials: K
authors.lastname: Sakurai
authors.forename: Saravanan
authors.initials: S
authors.lastname: Kolandaivelu
authors.forename: Alexander V
authors.initials: AV
authors.lastname: Kolesnikov
authors.forename: Astra
authors.initials: A
authors.lastname: Dinculescu
authors.forename: Jie
authors.initials: J
authors.lastname: Li
authors.forename: Ping
authors.initials: P
authors.lastname: Zhu
authors.forename: Xuan
authors.initials: X
authors.lastname: Liu
authors.forename: Jijing
authors.initials: J
authors.lastname: Pang
authors.forename: Vince A
authors.initials: VA
authors.lastname: Chiodo
authors.forename: Sanford L
authors.initials: SL
authors.lastname: Boye
authors.forename: Bo
authors.initials: B
authors.lastname: Chang
authors.forename: Visvanathan
authors.initials: V
authors.lastname: Ramamurthy
authors.forename: Vladimir J
authors.initials: VJ
authors.lastname: Kefalov
authors.forename: William W
authors.initials: WW
authors.lastname: Hauswirth
mesh_terms: D000818:Animals; D020134:Catalytic Domain; D054707:Cyclic Nucleotide Phosphodiesterases, Type 6 / Q000235:genetics / Q000378:metabolism*; D018014:Gene Transfer Techniques; D051379:Mice; D018345:Mice, Knockout; D018408:Patch-Clamp Techniques; D017949:Retinal Cone Photoreceptor Cells / Q000378:metabolism; D012162:Retinal Degeneration / Q000235:genetics / Q000378:metabolism; D017948:Retinal Rod Photoreceptor Cells / Q000378:metabolism*
chemical_list: D054707:Cyclic Nucleotide Phosphodiesterases, Type 6