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Implications of dimeric activation of PDE6 for rod phototransduction.

ABSTRACT: We examine the implications of a recent report providing evidence that two transducins must bind to the rod phosphodiesterase to elicit significant hydrolytic activity. To predict the rod photoreceptor's electrical response, we use numerical simulation of the two-dimensional diffusional contact of interacting molecules at the surface of the disc membrane, and then we use the simulated PDE activity as the driving function for the downstream reaction cascade. The results account for a number of aspects of rod phototransduction that have previously been puzzling. For example, they explain the existence of a greater initial delay in rods than in cones. Furthermore, our analysis suggests that the 'continuous' noise recorded in rods in darkness is likely to arise from spontaneous activation of individual molecules of PDE at a rate of a few tens per second per rod, probably as a consequence of spontaneous activation of transducins at a rate of thousands per second per rod. Hence, the dimeric activation of PDE in rods provides immunity against spontaneous transducin activation, thereby reducing the continuous noise. Our analysis also provides a coherent quantitative explanation of the amplification underlying the single photon response. Overall, numerical analysis of the dimeric activation of PDE places rod phototransduction in a new light.

SUBMITTER: Lamb TD

PROVIDER: S-EPMC6119862 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Implications of dimeric activation of PDE6 for rod phototransduction.

Lamb Trevor D TD Heck Martin M Kraft Timothy W TW

Open biology 20180801 8

We examine the implications of a recent report providing evidence that two transducins must bind to the rod phosphodiesterase to elicit significant hydrolytic activity. To predict the rod photoreceptor's electrical response, we use numerical simulation of the two-dimensional diffusional contact of interacting molecules at the surface of the disc membrane, and then we use the simulated PDE activity as the driving function for the downstream reaction cascade. The results account for a number of as ...[more]

PMID: 30068567

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Project description:Damage and loss of the postmitotic photoreceptors is a leading cause of blindness in many diseases of the eye. Although the mechanisms of photoreceptor death have been extensively studied, few studies have addressed mechanisms that help sustain these non-replicating neurons for the life of an organism. Autophagy is an intracellular pathway where cytoplasmic constituents are delivered to the lysosomal pathway for degradation. It is not only a major pathway activated in response to cellular stress, but is also important for cytoplasmic turnover and to supply the structural and energy needs of cells. We examined the importance of autophagy in photoreceptors by deleting the essential autophagy gene Atg5 specifically in rods. Loss of autophagy led to progressive degeneration of rod photoreceptors beginning at 8 weeks of age such that by 44 weeks few rods remained. Cone photoreceptor numbers were only slightly diminished following rod degeneration but their function was significantly decreased. Rod cell death was apoptotic but was not dependent on daily light exposure or accelerated by intense light. Although the light-regulated translocation of the phototransduction proteins arrestin and transducin were unaffected in rods lacking autophagy, Atg5-deficient rods accumulated transducin-? as they degenerated suggesting autophagy might regulate the level of this protein. This was confirmed when the light-induced decrease in transducin was abolished in Atg5-deficient rods and the inhibition of autophagy in retinal explants cultures prevented its degradation. These results demonstrate that basal autophagy is essential to the long-term health of rod photoreceptors and a critical process for maintaining optimal levels of the phototransduction protein transducin-?. As the lack of autophagy is associated with retinal degeneration and altered phototransduction protein degradation in the absence of harmful gene products, this process may be a viable therapeutic target where rod cell loss is the primary pathologic event.

Dataset Information

Implications of dimeric activation of PDE6 for rod phototransduction.

Publications

Implications of dimeric activation of PDE6 for rod phototransduction.

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