Disease relevance of Pde6h

• Stationary night blindness or progressive retinal degeneration in mice carrying different alleles of PDE gamma [1].
• PURPOSE: To generate an animal model of retinal degeneration by using AAV-mediated ribozyme knockdown of the gamma-subunit of the rod cGMP phosphodiesterase (PDEgamma) mRNA in the retina of wild-type mice [2].
• 3. We also report that PDEgamma translation from mRNA transcript is increased in cultured human pulmonary artery smooth muscle cells subjected to chronic hypoxia for 14 days [3].
• We have now investigated whether PDEgamma plays a role in modulating chronic hypoxic-dependent mitogenic signalling pathways in pulmonary smooth muscle from rats with pulmonary hypertension (PHT) [3].

High impact information on Pde6h

• The inhibitory gamma subunits of the retinal rod and cone photoreceptor type 6 retinal cyclic guanosine monophosphate phosphodiesterase (PDEgamma) are expressed in non-retinal tissues [4].
• We conclude that PDEgamma is an entirely novel intermediate regulating mitogenic signaling from both receptor tyrosine kinase and G-protein-coupled receptors in human embryonic kidney 293 cells [4].
• Retinal tissue analysis showed that loss of the photoreceptor cells and PDEgamma mRNA and protein paralleled the ERG results [2].
• Pdeg(tm1)/Pdeg(tm1) mice (which lack PDEgamma owing to a targeted disruption of the Pdeg gene) suffer from a very rapid and severe photoreceptor degeneration [5].
• Our results showed that wild-type PDEgamma and Y84G transgenes could complement the Pdeg(tm1)/Pdeg(tm1) mutant for photoreceptor survival [5].

Biological context of Pde6h

• However, the Y84G mutation did not fully eliminate the control of PDEgamma on the PDE catalytic core in vivo; the expression of the mutant subunit was associated with only a 10-fold reduction in the amplitude of the a-wave and a 1.5-fold decrease in the b-wave of the corneal electroretinogram [5].
• Here we describe the morphology and physiology of the retina in mice carrying four different Pdeg alleles: Pdeg(tm), Del 7C, Y84G, and W70A and the effect that these mutations of PDE gamma have on components of the activation and deactivation phases of phototransduction [1].
• A point mutation (W70A) in the rod PDE-gamma gene desensitizing and delaying murine rod photoreceptors [6].
• Comparison of the deduced amino acid sequences of the proteins from the three species indicates that PDE gamma has been very well conserved through evolution [7].

Anatomical context of Pde6h

• Here, we report that mouse lung expresses gamma-subunit (PDEgamma) transcripts of the rod and cone photoreceptor cGMP phosphodiesterase genes (Pde6g and Pde6h, respectively) [8].
• Second, the expression of p14 immunostained with antibodies recognizing both rod and cone PDEgamma was substantially reduced in lung membranes from Pde6g-/- mice [8].
• 2. We show for the first time that PDEgamma is expressed in rat main, first, intrapulmonary and resistance pulmonary arteries [3].

Physical interactions of Pde6h

• Immobilized PDE gamma binds transducin alpha subunit charged with GTP, PDE alpha and beta subunits, and, unexpectedly, arrestin (S-antigen) [9].

Regulatory relationships of Pde6h

• The addition of rod PDEgamma to the incubation completely blocked the cleavage of PDE6 by caspase-3 [10].

Other interactions of Pde6h

• To determine the effects of this mutation on in vivo function, the murine opsin promoter was used to direct expression to the photoreceptors of +/Pdeg(tm1) mice of a mutant Y84G and a wild-type PDEgamma control transgene [5].
• The carboxyl terminus of PDE gamma, involved in interaction with the catalytic subunits of cGMP-PDE and the alpha-subunit of transducin, is conserved through evolution [11].
• In contrast with both PDE6 and PDE5A1, rod PDEgamma was without effect on this enzyme [10].
• In contrast, rod PDEgamma converted PDE5A1 (molecular mass of 98 kDa) to a better substrate for caspase-3 [10].

Analytical, diagnostic and therapeutic context of Pde6h

• A gene-targeting approach was used to disrupt the mouse PDEgamma gene [12].
• Messenger RNA and protein levels of PDEgamma gene were monitored by reverse transcription-polymerase chain reaction (RT-PCR) and Western immunoblot assay [2].

References