PDE6

PDE6, or phosphodiesterase 6, is a family of cGMP-specific phosphodiesterases located in vertebrate photoreceptor cells of the retina. The enzyme exists in different forms: rods contain a heterotetramer with two catalytic subunits, PDE6A and PDE6B, plus two inhibitory gamma subunits, PDE6G. Cones use PDE6C as the catalytic subunit, together with the same gamma inhibitory subunit. PDE6 enzymes hydrolyze cGMP to GMP, thereby regulating the level of cGMP inside photoreceptors.

In darkness, high cGMP keeps cyclic-nucleotide-gated channels open, maintaining a depolarized state. Light activation triggers rhodopsin, which activates the G protein transducin. Transducin then stimulates PDE6, leading to rapid hydrolysis of cGMP, a fall in cGMP-gated channel conductance, hyperpolarization, and reduced neurotransmitter release from photoreceptors.

Genetic defects in PDE6 genes cause inherited retinal diseases. Mutations in PDE6A and PDE6B are major causes of autosomal recessive retinitis pigmentosa. PDE6C variants are associated with cone dystrophies and achromatopsia, while PDE6G variants have been linked to retinal degeneration in certain cases. PDE6-related diseases are typically progressive and primarily affect non-syndromic vision.

Therapeutic approaches are under investigation, including gene augmentation therapies using adeno-associated virus vectors to restore PDE6 function in affected photoreceptors. Ongoing research seeks to clarify genotype–phenotype correlations and to develop treatments that preserve both rod and cone vision.