PDE6B

Rod cGMP-specific 3',5'-cyclic phosphodiesterase subunit beta is the beta subunit of the protein complex PDE6 that is encoded by the PDE6B is_associated_with::gene. PDE6 is crucial in transmission and amplification of visual signal. The existence of this beta subunit is essential for normal PDE6 functioning. Mutations in this subunit are responsible for retinal degeneration such as is_associated_with::retinitis pigmentosa or congenital stationary is_associated_with::night blindness.

Structure
PDE6 is a protein complex located on the photoreceptor's outer segment, and plays an important role in the is_associated_with::phototransduction cascade. There are two types of photoreceptors: cones and rods. The rod and cone PDE6 complexes have different structures. PDE6β together with PDE6α and two identical inhibitory subunits, PDE6γ, form the rod PDE6 is_associated_with::holoenzyme while the cone PDE6 complex only consists of two identical PDE6α' catalytic subunits. PDE6β, one of the catalytic units in rod PDE6, is composed of three domains: two is_associated_with::N-terminal is_associated_with::GAF domains and one is_associated_with::C-terminal catalytic domain.The non-catalytic GAF domains are responsible for is_associated_with::cGMP binding. The C-terminal interacts with cell membrane by is_associated_with::isoprenylation and S-carboxylmethylation.

Function
Absorption of photons by is_associated_with::rhodopsin triggers a is_associated_with::signal transduction cascade in rod photoreceptors. This is_associated_with::phototransduction cascade leads to hydrolysis of cGMP by cGMP-is_associated_with::phosphodiesterase (PDE) that closes cGMP-gated channels and hyperpolarizes the cell. PDE6β is necessary for the formation of a functional phosphodiesterase holoenzyme.

Function of PDE6
PDE6 is a highly concentrated protein in retinal photoreceptors. With the presence of the GAF domain, PDE6 can actively bind to the cGMP. The inactive PDE6 in the dark allows cGMP to bind to cGMP gated ion channels. The channel remains open as long as cGMP is binding to it, which allows constant electron flow in to the photoreceptor cell through the is_associated_with::plasma membrane. Light causes the visual pigment, is_associated_with::rhodopsin, to activate. This process leads to the release of subunit PDE6γ from PDE6αβ, activating PDE6 which leads to the is_associated_with::hydrolysis of cGMP. Without the cGMP binding, the ion channel closes, leading to the hyperpolarization. After hyperpolarization the presnaptic transimitter is reduced. Next, the enzyme is_associated_with::guanylate cyclase restores cGMP, which reopens the membrane channels. This process is called light adaptation.

Function of PDE6B
PDE6β is the only protein that undergoes the two types of is_associated_with::post-translational modification, is_associated_with::prenylation and is_associated_with::carboxymethylation. The is_associated_with::geranylgeranyl group of PDE6B is the result of these modifications, which are responsible for the rod PDE6's interaction with membrane.

rd1 mouse
Mutation of the PDE6b gene leads to the dysfunction of PDE, which results in failure of hydrolysis of cGMP. The rd1 mouse is a well-characterized animal model of retinitis pigmentosa caused by the mutation of Pde6b gene. The phenotype was first discovered in rodless mice in the 1920's by Keeler. An insertion of Murine leukemia is_associated_with::provirus is present near the first is_associated_with::exon combined with a point mutation, which introduces a stop codon in exon 7. In addition to the rd1 mouse, a missense mutation (R560C) in exon 13 of the Pde6b gene is the character of another animal model of recessive retinal degeneration.

In rd1 animals, the retinal rod photoreceptor cells begin degenerating at about postnatal day 10, and by 3 weeks no rod photoreceptors remain. Degeneration is preceded by accumulation of cGMP in the retina and is correlated with deficient activity of the rod photoreceptor cGMP-phosphodiesterase. Cone photoreceptors undergo a slower degeneration over the course of a year, which causes the mutants to completely go blind. The possibility of altering the course of retinal degeneration through subretinal injection of recombinant replication defective is_associated_with::adenovirus that contained the murine cDNA for wildtype PDE6β was tested in rd1 mice. Subretinal injection of rd1 mice was carried out 4 days after birth, before the onset of rod photoreceptor degeneration. Following therapy, Pde6β transcripts and enzyme activity were detected, and histologic studies revealed that photoreceptor cell death was significantly retarded.

rcd1 dog
Similar to rd1 in mice, Rod-cone dysplasia type 1 (rcd1-PRA) is a form of is_associated_with::progressive retinal atrophy (PRA), with early onset of the disease. The is_associated_with::Irish Setter is a characterized animal model of rcd1. The mutation is caused by a nonsense mutation in pde6b gene. Photoreceptors start degeneration at postnatal day 13 until a year after the dog is totally blind.