Reproducibility of the Rod Photoreceptor Response Depends Critically on the Concentration of the Phosphodiesterase Effector Enzyme
| Autor: | Ala Morshedian, Gabriela Sendek, Sze Yin Ng, Kimberly Boyd, Roxana A. Radu, Mingyao Liu, Nikolai O. Artemyev, Alapakkam P. Sampath, Gordon L. Fain |
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| Rok vydání: | 2022 |
| Předmět: |
rod photoreceptor
Neurology & Neurosurgery Phosphoric Diester Hydrolases General Neuroscience Psychology and Cognitive Sciences Neurosciences Reproducibility of Results Neurodegenerative sensitivity transduction Medical and Health Sciences Retina Mice GAF A domain Retinal Rod Photoreceptor Cells Animals 2.1 Biological and endogenous factors Aetiology single-photon response Cyclic GMP phosphodiesterase Eye Disease and Disorders of Vision Research Articles |
| Zdroj: | The Journal of neuroscience : the official journal of the Society for Neuroscience, vol 42, iss 11 J Neurosci |
| ISSN: | 1529-2401 0270-6474 |
| DOI: | 10.1523/jneurosci.2119-21.2021 |
| Popis: | The high sensitivity of night vision requires that rod photoreceptors reliably and reproducibly signal the absorption of single photons, a process that depends on tight regulation of intracellular cGMP concentration through the phototransduction cascade. Here in the mouse (Mus musculus), we studied a single-siteD167Amutation of the gene for the α subunit of rod photoreceptor phosphodiesterase (PDEA), made with the aim of removing a noncatalytic binding site for cGMP. This mutation unexpectedly eliminated nearly all PDEA expression and reduced expression of the β subunit (PDEB) to ∼5%-10% of WT. The remaining PDE had nearly normal specific activity; degeneration was slow, with 50%-60% of rods remaining after 6 months. Responses were larger and more sensitive than normal but slower in rise and decay, probably from slower dark turnover of cGMP. Remarkably, responses became much less reproducible than WT, with response variance increasing for amplitude by over 10-fold, and for latency and time-to-peak by >100-fold. We hypothesize that the increase in variance is the result of greater variability in the dark-resting concentration of cGMP, produced by spatial and temporal nonuniformity in spontaneous PDE activity. This variability decreased as stimuli were made brighter, presumably because of greater spatial uniformity of phototransduction and the approach to saturation. We conclude that the constancy of the rod response depends critically on PDE expression to maintain adequate spontaneous PDE activity, so that the concentration of second messenger is relatively uniform throughout the outer segment.SIGNIFICANCE STATEMENTRod photoreceptors in the vertebrate retina reliably signal the absorption of single photons of light by generating responses that are remarkably reproducible in amplitude and waveform. We show that this reproducibility depends critically on the concentration of the effector enzyme phosphodiesterase (PDE), which metabolizes the second messenger cGMP and generates rod light responses. In rods with theD167Amutation of the α subunit of PDE, only 5%-10% of PDE is expressed. Single-photon responses then become much more variable than in WT rods. We think this variability is caused by spatial and temporal inhomogeneity in the concentration of cGMP in darkness, so that photons absorbed in different parts of the cell produce responses of greatly varying amplitude and waveform. |
| Databáze: | OpenAIRE |
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