Cone phosphodiesterase-6α′ restores rod function and confers distinct physiological properties in the rod phosphodiesterase-6β-deficient rd10 mouse

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 PDE6′ can couple effectively to the rod phototransduction pathway.Wealso 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.