Disease relevance of Pdc

• Light sensitivity and adaptation, general characteristics of rod photoreceptor cell vision, allow rods to modulate their response depending on the lighting environment to which they are exposed [1].
• Retinal accumulation of the phosducin/T beta gamma and transducin complexes in developing normal mice and in mice and dogs with inherited retinal degeneration [2].
• The data indicate that CaMKII expression/activity in amacrine and ganglion cells is negatively regulated by the rod photoreceptor-mediated visual input [3].
• Retinitis pigmentosa (RP) is a label for a group of diseases caused by a large number of mutations that result in rod photoreceptor cell death followed by gradual death of cones [4].
• Using recombinant baculovirus vectors, the three subunits of mouse rod photoreceptor cGMP phosphodiesterase (PDE) (alpha beta gamma 2) have been expressed in insect cells [5].

High impact information on Pdc

• Rb regulates proliferation and rod photoreceptor development in the mouse retina [6].
• Nrl is required for rod photoreceptor development [7].
• Rom-1 is required for rod photoreceptor viability and the regulation of disk morphogenesis [8].
• Crystal structure at 2.4 angstroms resolution of the complex of transducin betagamma and its regulator, phosducin [9].
• We conclude that the mouse rd locus encodes the rod photoreceptor cGMP-phosphodiesterase beta subunit [10].

Chemical compound and disease context of Pdc

• In this study we have examined the consequences of activating the PHD oxygen-sensing pathway in cultured neonatal myocytes using ethyl-3,4 dihydroxybenzoate and dimethyloxalylglycine, inhibitors that, similar to hypoxia, inhibit this family of O2-dependent PHD enzymes [11].
• Since alterations in glutamate metabolism have been described in different models of retinitis pigmentosa, we investigated in the present work whether changes in glutamate turnover occur in the degenerating rd1 retina and whether glutamate-mediated excitotoxic mechanisms may contribute to rod photoreceptor death in this model [12].

Biological context of Pdc

• Phosducin (Pd), a principal protein of retinal photoreceptor cells, modulates the phototransduction cascade by interacting with transducin [13].
• Deduced Pd amino acid sequences were highly homologous to those of human, bovine and rat [13].
• Gene Pd is 15 kb in length and has four exons [13].
• Rat pineal phosducin has a single consensus phosphorylation domain for protein kinase A that is nearly identical to that of retinal phosducin, which is phosphorylated by protein kinase A in situ [14].
• In keeping with a proposed role of retinal phosducin in down-regulation of the photo-transduction cascade, a modulatory role in signal transduction is proposed for pineal phosducin [14].

Anatomical context of Pdc

• Phosducin facilitates light-driven transducin translocation in rod photoreceptors. Evidence from the phosducin knockout mouse [15].
• Rat pineal gland phosducin: cDNA isolation, nucleotide sequence, and chromosomal assignment in the mouse [14].
• Cytoskeleton participation in subcellular trafficking of signal transduction proteins in rod photoreceptor cells [1].
• Transducin null (Tr alpha-/-) mice lack rod photoreceptor activity and thus remaining retinal circuits are solely generated via cone photoreceptor activity [16].
• Differential modification of phosducin protein in degenerating rd1 retina is associated with constitutively active Ca2+/calmodulin kinase II in rod outer segments [17].

Associations of Pdc with chemical compounds

• A 1217-nucleotide cDNA was isolated from a rat pineal library by DNA-DNA hybridization with a polymerase chain reaction-amplified cDNA of bovine retina mRNA for phosducin [14].
• Degeneration is preceded by accumulation of cyclic GMP in the retina and is correlated with deficient activity of the rod photoreceptor cGMP-phosphodiesterase [10].
• In the developing retina, inhibition of glycine receptor activity prevents proper rod photoreceptor development [18].
• Recently an oxygen-sensing/transducing mechanism has been identified as a family of O2-dependent prolyl hydroxylase domain-containing enzymes (PHD) [11].
• In normoxia, PHD hydroxylates a specific proline residue that directs the degradation of constitutively synthesized hypoxia-inducible factor-1alpha [11].
• We found that in the dark-adapted rods, phosducin phosphorylated at serine 54 is compartmentalized predominantly in the ellipsoid and outer segment compartments [19].

Physical interactions of Pdc

• First, we have demonstrated that transducin beta gamma subunits interact with phosducin along their entire intracellular translocation route, as evident from their co-precipitation in serial tangential sections from light-adapted but not dark-adapted retinas [15].
• The gamma subunit of the rod photoreceptor cGMP phosphodiesterase can modulate the proteolysis of two cGMP binding cGMP-specific phosphodiesterases (PDE6 and PDE5) by caspase-3 [20].

Regulatory relationships of Pdc

• Ciliary neurotrophic factor (CNTF) has been known to inhibit the differentiation of presumptive rod photoreceptor cells; however, the underlying mechanisms have remained to be elucidated [21].
• RET52 localization, developmental expression, homologies to dematin, and in vitro phosphorylation pattern suggest a possible role for cytoskeleton-associated proteins in the initiation or control of disk membrane assembly and/or synapse formation in the rod photoreceptor [22].
• Most recent studies reveal that cytosolic components like phosducin and arrestin interfere with receptor internalization, that is phosducin impairs receptor phosphorylation and arrestin enhances endocytosis by uncoupling the receptor from its G protein [23].

Other interactions of Pdc

• Second, we generated a phosducin knockout mouse and found that the degree of light-driven transducin translocation in the rods of these mice was significantly reduced as compared with that observed in the rods of wild type animals [15].
• We expressed the gamma subunit of mouse rod photoreceptor cGMP phosphodiesterase (PDE) in the bacterial pGFX-2TK expression vector which produces a cleavable 40 kDa fusion protein [24].
• Phosducin is found exclusively in photoreceptor cells, including the synaptic and nuclear layers, while phosducin-like protein is found throughout the inner retinal layers, most abundantly in the bipolar cells of the inner nuclear layer [25].
• The increased rd1 phosducin phosphorylation coincided with increased activation of calcium/calmodulin-activated protein kinase II, which is known to utilize phosducin as a substrate [17].
• We also demonstrated that STAT3 activation in presumptive rod photoreceptor cells at E18.5 is rapidly downregulated at P0, when Rhodopsin expression starts during retinal development [21].

Analytical, diagnostic and therapeutic context of Pdc

• Northern blot analysis demonstrates that the mRNA for phosducin is approximately 1.3 kb in both rat pineal and rat retina [14].
• Western blot analysis detected immunoreactivity both for phosducin and T beta in retinal homogenates of 3-day-old mice [2].
• Gel filtration analysis of extracts from immature mouse retina showed that phosducin and T beta co-eluted, like the phosducin/T beta gamma complex of adult retina, as a 77-kDa complex, indicating that the phosducin/T beta gamma complex is formed when photoreceptors first synthesize the components of the complex [2].
• Microinjection of phosducin, however, did not inhibit the fertilization-induced modifications of the zona pellucida and microinjection of beta gamma t did not result in egg activation in the absence of sperm [26].
• Coculture of transgenic mouse with wild-type mouse or rat retinal cells significantly enhanced transgenic rod photoreceptor survival; this survival-promoting activity was diffusible through a filter, was heat labile, and not present in transgenic retinal cells [27].

References