Dataset Information

It takes two transducins to activate the cGMP-phosphodiesterase 6 in retinal rods.

ABSTRACT: Among cyclic nucleotide phosphodiesterases (PDEs), PDE6 is unique in serving as an effector enzyme in G protein-coupled signal transduction. In retinal rods and cones, PDE6 is membrane-bound and activated to hydrolyse its substrate, cGMP, by binding of two active G protein ?-subunits (G?*). To investigate the activation mechanism of mammalian rod PDE6, we have collected functional and structural data, and analysed them by reaction-diffusion simulations. G?* titration of membrane-bound PDE6 reveals a strong functional asymmetry of the enzyme with respect to the affinity of G?* for its two binding sites on membrane-bound PDE6 and the enzymatic activity of the intermediary 1 : 1 G?* · PDE6 complex. Employing cGMP and its 8-bromo analogue as substrates, we find that G?* · PDE6 forms with high affinity but has virtually no cGMP hydrolytic activity. To fully activate PDE6, it takes a second copy of G?* which binds with lower affinity, forming G?* · PDE6 · G?*. Reaction-diffusion simulations show that the functional asymmetry of membrane-bound PDE6 constitutes a coincidence switch and explains the lack of G protein-related noise in visual signal transduction. The high local concentration of G?* generated by a light-activated rhodopsin molecule efficiently activates PDE6, whereas the low density of spontaneously activated G?* fails to activate the effector enzyme.

SUBMITTER: Qureshi BM

PROVIDER: S-EPMC6119865 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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It takes two transducins to activate the cGMP-phosphodiesterase 6 in retinal rods.

Qureshi Bilal M BM Behrmann Elmar E Schöneberg Johannes J Loerke Justus J Bürger Jörg J Mielke Thorsten T Giesebrecht Jan J Noé Frank F Lamb Trevor D TD Hofmann Klaus Peter KP Spahn Christian M T CMT Heck Martin M

Open biology 20180801 8

Among cyclic nucleotide phosphodiesterases (PDEs), PDE6 is unique in serving as an effector enzyme in G protein-coupled signal transduction. In retinal rods and cones, PDE6 is membrane-bound and activated to hydrolyse its substrate, cGMP, by binding of two active G protein α-subunits (Gα*). To investigate the activation mechanism of mammalian rod PDE6, we have collected functional and structural data, and analysed them by reaction-diffusion simulations. Gα* titration of membrane-bound PDE6 revea ...[more]

PMID: 30068566

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Project description:We report the chromosomal localization, mutant gene identification, ophthalmic appearance, histology, and functional analysis of two new hereditary mouse models of retinal degeneration not having the Pde6brd1("r", "rd", or "rodless") mutation. One strain harbors an autosomal recessive mutation that maps to mouse chromosome 5. Sequence analysis showed that the retinal degeneration is caused by a missense point mutation in exon 13 of the beta-subunit of the rod cGMP phosphodiesterase (beta-PDE) gene (Pde6b). The gene symbol for this strain was set as Pde6brd10, abbreviated rd10 hereafter. Mice homozygous for the rd10 mutation showed histological changes at postnatal day 16 (P16) of age and sclerotic retinal vessels at four weeks of age, consistent with retinal degeneration. Retinal sections were highly positive for TUNEL and activated caspase-3 immunoreactivity, specifically in the outer nuclear layer (ONL). ERGs were never normal, but rod and cone ERG a- and b-waves were easily measured at P18 and steadily declined over 90% by two months of age. Protein extracts from rd10 retinas were positive for beta-PDE immunoreactivity starting at about the same time as wild-type (P10), though signal averaged less than 40% of wild-type. Interestingly, rearing rd10 mice in total darkness delayed degeneration for at least a week, after which morphological and functional loss progressed irregularly. With the second strain, a complementation test with rd1 mice revealed that the retinal degeneration phenotype observed represents a possible new allele of Pde6b. Sequencing demonstrated a missense point mutation in exon 16 of the beta-subunit of rod phosphodiesterase gene, different from the point mutations in rd1 and rd10. The gene symbol for this strain was set as Pde6bnmf137, abbreviated nmf137 hereafter. Mice homozygous for this mutation showed retinal degeneration with a mottled retina and white retinal vessels at three weeks of age. The exon 13 missense mutation (rd10) is the first known occurrence of a second mutant allele spontaneously arising in the Pde6b gene in mice and may provide a model for studying the pathogenesis of autosomal recessive retinitis pigmentosa (arRP) in humans. It may also provide a better model for experimental pharmaceutical-based therapy for RP because of its later onset and milder retinal degeneration than rd1 and nmf137.

Dataset Information

It takes two transducins to activate the cGMP-phosphodiesterase 6 in retinal rods.

Publications

It takes two transducins to activate the cGMP-phosphodiesterase 6 in retinal rods.

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