Rod cGMP-specific 3',5'-cyclic phosphodiesterase subunit beta is the beta subunit of the protein complex PDE6 that is encoded by the PDE6B gene. [5] [6] 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 retinitis pigmentosa [7] [8] or congenital stationary night blindness. [9]
PDE6 is a protein complex located on the photoreceptor's outer segment, and plays an important role in the phototransduction cascade. [10] 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 holoenzyme [11] while the cone PDE6 complex only consists of two identical PDE6α' catalytic subunits. [12] PDE6β, one of the catalytic units in rod PDE6, is composed of three domains: two N-terminal GAF domains and one C-terminal catalytic domain. [13] The non-catalytic GAF domains are responsible for cGMP binding. The C-terminal interacts with cell membrane by isoprenylation and S-carboxylmethylation. [12]
Absorption of photons by rhodopsin triggers a signal transduction cascade in rod photoreceptors. This phototransduction cascade leads to hydrolysis of cGMP by cGMP-phosphodiesterase (PDE) that closes cGMP-gated channels and hyperpolarizes the cell. [14] PDE6β is necessary for the formation of a functional phosphodiesterase holoenzyme. [12]
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 plasma membrane. Light causes the visual pigment, rhodopsin, to activate. This process leads to the release of subunit PDE6γ from PDE6αβ, activating PDE6 which leads to the hydrolysis of cGMP. Without the cGMP binding, the ion channel closes, leading to the hyperpolarization. [12] After hyperpolarization the presnaptic transmitter is reduced. Next, the enzyme guanylate cyclase restores cGMP, which reopens the membrane channels. This process is called light adaptation.
PDE6β is the only protein that undergoes the two types of post-translational modification, prenylation and carboxymethylation. [15] The geranylgeranyl group of PDE6B is the result of these modifications, which are responsible for the rod PDE6's interaction with membrane.
The figure at left shows the PDE6 aalpha/beta dimer in blue and purple, with the gamma ubunits in green and orange.
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. [16] The phenotype was first discovered in rodless mice in the 1920s by Keeler. [17] An insertion of Murine leukemia provirus is present near the first 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. [16] [18] Cone photoreceptors undergo a slower degeneration over the course of a year, which causes the mutants to completely go blind. [19] The possibility of altering the course of retinal degeneration through subretinal injection of recombinant replication defective adenovirus that contained the murine cDNA for wildtype PDE6β was tested in rd1 mice. [20] 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. [6]
The albino FVB mouse laboratory strain become blind by weaning age due to a mutant allele of the PDE6b gene. There are pigmented derivative strains of FVB that lack this trait.
Similar to rd1 in mice, Rod-cone dysplasia type 1 (rcd1-PRA) is a form of progressive retinal atrophy (PRA), with early onset of the disease. The 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. [21]
Rhodopsin, also known as visual purple, is a protein encoded by the RHO gene and a G-protein-coupled receptor (GPCR). It is the opsin of the rod cells in the retina and a light-sensitive receptor protein that triggers visual phototransduction in rods. Rhodopsin mediates dim light vision and thus is extremely sensitive to light. When rhodopsin is exposed to light, it immediately photobleaches. In humans, it is regenerated fully in about 30 minutes, after which the rods are more sensitive. Defects in the rhodopsin gene cause eye diseases such as retinitis pigmentosa and congenital stationary night blindness.
Retinitis pigmentosa (RP) is a genetic disorder of the eyes that causes loss of vision. Symptoms include trouble seeing at night and decreasing peripheral vision. As peripheral vision worsens, people may experience "tunnel vision". Complete blindness is uncommon. Onset of symptoms is generally gradual and often begins in childhood.
Cyclic nucleotide–gated ion channels or CNG channels are ion channels that function in response to the binding of cyclic nucleotides. CNG channels are nonselective cation channels that are found in the membranes of various tissue and cell types, and are significant in sensory transduction as well as cellular development. Their function can be the result of a combination of the binding of cyclic nucleotides and either a depolarization or a hyperpolarization event. Initially discovered in the cells that make up the retina of the eye, CNG channels have been found in many different cell types across both the animal and the plant kingdoms. CNG channels have a very complex structure with various subunits and domains that play a critical role in their function. CNG channels are significant in the function of various sensory pathways including vision and olfaction, as well as in other key cellular functions such as hormone release and chemotaxis. CNG channels have also been found to exist in prokaryotes, including many spirochaeta, though their precise role in bacterial physiology remains unknown.
Progressive retinal atrophy (PRA) is a group of genetic diseases seen in certain breeds of dogs and, more rarely, cats. Similar to retinitis pigmentosa in humans, it is characterized by the bilateral degeneration of the retina, causing progressive vision loss culminating in blindness. The condition in nearly all breeds is inherited as an autosomal recessive trait, with the exception of the Siberian Husky (inherited as an X chromosome linked trait) and the Bullmastiff (inherited as an autosomal dominant trait). There is no treatment.
The photoreceptor cell-specific nuclear receptor (PNR), also known as NR2E3, is a protein that in humans is encoded by the NR2E3 gene. PNR is a member of the nuclear receptor super family of intracellular transcription factors.
X-linked retinitis pigmentosa GTPase regulator is a GTPase-binding protein that in humans is encoded by the RPGR gene. The gene is located on the X-chromosome and is commonly associated with X-linked retinitis pigmentosa (XLRP). In photoreceptor cells, RPGR is localized in the connecting cilium which connects the protein-synthesizing inner segment to the photosensitive outer segment and is involved in the modulation of cargo trafficked between the two segments.
ATP-binding cassette, sub-family A (ABC1), member 4, also known as ABCA4 or ABCR, is a protein which in humans is encoded by the ABCA4 gene.
Peripherin-2 is a protein, that in humans is encoded by the PRPH2 gene. Peripherin-2 is found in the rod and cone cells of the retina of the eye. Defects in this protein result in one form of retinitis pigmentosa, an incurable blindness.
Cone-rod homeobox protein is a protein that in humans is encoded by the CRX gene.
Neural retina-specific leucine zipper protein is a protein that in humans is encoded by the NRL gene.
Retinal rod rhodopsin-sensitive cGMP 3',5'-cyclic phosphodiesterase subunit gamma is an enzyme that in humans is encoded by the PDE6G gene.
Cyclic nucleotide gated channel beta 3, also known as CNGB3, is a human gene encoding an ion channel protein.
Tubby-related protein 1 is a protein that in humans is encoded by the TULP1 gene.
Cyclic nucleotide-gated channel alpha 1, also known as CNGA1, is a human gene encoding an ion channel protein. Heterologously expressed CNGA1 can form a functional channel that is permeable to calcium. In rod photoreceptors, however, CNGA1 forms a heterotetramer with CNGB1 in a 3:1 ratio. The addition of the CNGB1 channel imparts altered properties including more rapid channel kinetics and greater cAMP-activated current. When light hits rod photoreceptors, cGMP concentrations decrease causing rapid closure of CNGA1/B1 channels and, therefore, hyperpolarization of the membrane potential.
Rod outer segment membrane protein 1 is a protein that in humans is encoded by the ROM1 gene.
Oxygen-regulated protein 1 also known as retinitis pigmentosa 1 protein (RP1) is a protein that in humans is encoded by the RP1 gene.
Retinal rod rhodopsin-sensitive cGMP 3',5'-cyclic phosphodiesterase subunit delta is an enzyme that in humans is encoded by the PDE6D gene. PDE6D was originally identified as a fourth subunit of rod cell-specific cGMP phosphodiesterase (PDE). The precise function of PDE delta subunit in the rod specific GMP-PDE complex is unclear. In addition, PDE delta subunit is not confined to photoreceptor cells but is widely distributed in different tissues. PDE delta subunit is thought to be a specific soluble transport factor for certain prenylated proteins and Arl2-GTP a regulator of PDE-mediated transport.
Cyclic nucleotide gated channel beta 1, also known as CNGB1, is a human gene encoding an ion channel protein.
Rod cGMP-specific 3',5'-cyclic phosphodiesterase subunit alpha is an enzyme that in humans is encoded by the PDE6A gene.
Retinal degeneration is a retinopathy which consists in the deterioration of the retina caused by the progressive death of its cells. There are several reasons for retinal degeneration, including artery or vein occlusion, diabetic retinopathy, R.L.F./R.O.P., or disease. These may present in many different ways such as impaired vision, night blindness, retinal detachment, light sensitivity, tunnel vision, and loss of peripheral vision to total loss of vision. Of the retinal degenerative diseases retinitis pigmentosa (RP) is a very important example.
