Vision begins when a visual pigment molecule (opsin) absorbs a photon of light within a retinal photoreceptor cell. The photoexcited opsin then activates hundreds of heterotrimeric G-proteins (transducin). Activated transducin, in turn, binds to and activates a cyclic nucleotide phosphodiesterase (PDE6). As a result of PDE6 activation, cyclic GMP (cGMP) levels in the photoreceptor fall rapidly, causing closure of cGMP-gated ion channels in the plasma membrane. The transient hyperpolarization of the cell membrane that results from this enzyme cascade generates the electrical response that is propagated to other retinal neurons and, ultimately, to the brain.

PDE6 is the central effector enzyme of the phototransduction cascade in the outer segments of rod and cone photoreceptors. PDE6 activation and inactivation must be exquisitely regulated to control the excitation, recovery and adaptational phases of the photoresponse in rods and cones. The rod PDE6 holoenzyme consists of two non-identical catalytic subunits that form a dimer, plus two inhibitory subunits that black the catalytic site when PDE is not activated. Cone PDE6 contains homologous catalytic and inhibitory subunits, but differences in the amino acid sequences of the rod and cone subunits may confer different catalytic or regulatory properties.

The photoreceptor PDE6 family is one of five PDE families to contain cGMP-binding regulatory domains (GAF domains). Of the five GAF-containing PDEs, photoreceptor PDE6 is most similar in sequence, enzymological and pharmacological properties to PDE5. The recent success of pharmacological agents (Viagra, Cialis, Levitra) targeting PDE5 for the treatment of erectile dysfunction has focused attention on the similarities of the catalytic sites of PDE5 and PDE6. With few exceptions, drugs showing a high affinity for inhibition of PDE5 are non-selective for PDE6, leading to questions about side-effects of PDE5 inhibitors on visual function.

Defects in the structure and/or function of PDE6 have been shown to cause retinal degeneration resulting in vision impairment and blindness. Our research on the structure, function, and regulation of photoreceptor PDE6 will hopefully provide new insights and strategies for therapeutic intervention, either with PDE6 directly or with one or more PDE6-interacting proteins that modulate its function in rod and cone photoreceptors.