Effect of the ILE86TER mutation in the γ subunit of cGMP phosphodiesterase (PDE6) on rod photoreceptor signaling

Tsang, Stephen H.; Woodruff, Michael L.; Lin, Chyuan‐Sheng; Jacobson, Barry D.; Naumann, Matthew C.; Hsu, Chun Wei; Davis, R. J.; Cilluffo, Marianne; Chen, Jeannie; Fain, Gordon

doi:10.1016/j.cellsig.2011.08.021

Cited by 7 publications

(6 citation statements)

References 44 publications

(70 reference statements)

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“…Finally, several retinal disorders, such as stationary night blindness and retinal degeneration, are known to be linked to missense mutations that lead to the loss of inhibition of PDE6 in rods by its regulatory subunits PDE6 γ [81–83]. To test whether the model with these parameters would reproduce these findings in a cone geometry, dark activity of PDE was incrementally increased, and TPR was simulated (S1 Appendix).…”

Section: Resultsmentioning

confidence: 99%

Multi-scale, numerical modeling of spatio-temporal signaling in cone phototransduction

et al. 2019

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Mammals have two types of photoreceptors, rods and cones. While rods are exceptionally sensitive and mediate vision at very low illumination levels, cones operate in daylight and are responsible for the bulk of visual perception in most diurnal animals, including humans. Yet the mechanisms of phototransduction in cones is understudied, largely due to unavailability of pure cone outer segment (COS) preparations. Here we present a novel mathematical model of cone phototransduction that explicitly takes into account complex cone geometry and its multiple physical scales, faithfully reproduces features of the cone response, and is orders of magnitude more efficient than the standard 3D diffusion model. This is accomplished through the mathematical techniques of homogenization and concentrated capacity. The homogenized model is then computationally implemented by finite element method. This homogenized model permits one to analyze the effects of COS geometry on visual transduction and lends itself to performing large numbers of numerical trials, as required for parameter analysis and the stochasticity of rod and cone signal transduction. Agreement between the nonhomogenized, (i.e., standard 3D), and homogenized diffusion models is reported along with their simulation times and memory costs. Virtual expression of rod biochemistry on cone morphology is also presented for understanding some of the characteristic differences between rods and cones. These simulations evidence that 3D cone morphology and ion channel localization contribute to biphasic flash response, i.e undershoot. The 3D nonhomogenized and homogenized models are contrasted with more traditional and coarser well-stirred and 1D longitudinal diffusion models. The latter are single-scale and do not explicitly account for the multi-scale geometry of the COS, unlike the 3D homogenized model. We show that simpler models exaggerate the magnitude of the current suppression, yield accelerated time to peak, and do not predict the local concentration of cGMP at the ionic channels.

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Section: Resultsmentioning

confidence: 99%

Multi-scale, numerical modeling of spatio-temporal signaling in cone phototransduction

et al. 2019

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“…The P␥ subunit of PDE6 is essential for the folding and/or assembly of the latter; in the absence of P␥, virtually no functional PDE6 is formed in mouse photoreceptors, and this leads to rapid retinal degeneration (39). Moreover, in mice bearing a mutation that deletes just two C-terminal Ile residues of P␥, levels of the catalytic subunits of PDE6 are reduced in the retina (40). Recently, it was discovered that P␥ interacts with AIPL1, an obligate chaperone of PDE6; subsequently, it was hypothesized that this interaction markedly potentiates expression of functional PDE6C in a heterologous system and in photoreceptor cells in vivo (12,24).…”

Section: Discussionmentioning

confidence: 99%

Interaction of the tetratricopeptide repeat domain of aryl hydrocarbon receptor–interacting protein–like 1 with the regulatory Pγ subunit of phosphodiesterase 6

Yadav

Boyd

et al. 2019

Journal of Biological Chemistry

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Edited by Wolfgang Peti Phosphodiesterase-6 (PDE6) is key to both phototransduction and health of rods and cones. Proper folding of PDE6 relies on the chaperone activity of aryl hydrocarbon receptorinteracting protein-like 1 (AIPL1), and mutations in both PDE6 and AIPL1 can cause a severe form of blindness. Although AIPL1 and PDE6 are known to interact via the FK506-binding protein domain of AIPL1, the contribution of the tetratricopeptide repeat (TPR) domain of AIPL1 to its chaperone function is poorly understood. Here, we demonstrate that AIPL1-TPR interacts specifically with the regulatory P␥ subunit of PDE6. Use of NMR chemical shift perturbation (CSP) mapping technique revealed the interface between the C-terminal portion of P␥ and AIPL1-TPR. Our solution of the crystal structure of the AIPL1-TPR domain provided additional information, which together with the CSP data enabled us to generate a model of this interface. Biochemical analysis of chimeric AIPL1-AIP proteins supported this model and also revealed a correlation between the affinity of AIPL1-TPR for P␥ and the ability of P␥ to potentiate the chaperone activity of AIPL1. Based on these results, we present a model of the larger AIPL1-PDE6 complex. This supports the importance of simultaneous interactions of AIPL1-FK506-binding protein with the prenyl moieties of PDE6 and AIPL1-TPR with the P␥ subunit during the folding and/or assembly of PDE6. This study sheds new light on the versatility of TPR domains in protein folding by describing a novel TPR-protein binding partner, P␥, and revealing that this subunit imparts AIPL1 selectivity for its client.

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“…A similar observation was made for Grb14 − / − rods 15 . It is likely that feedback from the very active guanylyl cyclase in mouse rods acts to minimize the rise in circulating current by altering the concentration of cGMP (see for example reference 43 ). Future experiments with IR knock-down rods lacking the GCAP proteins may resolve this apparent discrepancy.…”

Section: Discussionmentioning

confidence: 99%

Effect of Knocking Down the Insulin Receptor on Mouse Rod Responses

Woodruff

Rajala

Fain

et al. 2015

Sci Rep

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Previous experiments have shown that the insulin receptor (IR) is expressed in mammalian rods and contributes to the protection of photoreceptors during bright-light exposure. The role of the insulin receptor in the production of the light response is however unknown. We have used suction-electrode recording to examine the responses of rods after conditionally knocking down the insulin receptor. Our results show that these IR knock-down rods have an accelerated decay of the light response and a small decrease in sensitivity by comparison to littermate WT rods. Our results indicate that the insulin receptor may have some role in controlling the rate of rod response decay, but they exclude a major role of the insulin receptor pathway in phototransduction.

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Effect of the ILE86TER mutation in the γ subunit of cGMP phosphodiesterase (PDE6) on rod photoreceptor signaling

Cited by 7 publications

References 44 publications

Multi-scale, numerical modeling of spatio-temporal signaling in cone phototransduction

Multi-scale, numerical modeling of spatio-temporal signaling in cone phototransduction

Interaction of the tetratricopeptide repeat domain of aryl hydrocarbon receptor–interacting protein–like 1 with the regulatory Pγ subunit of phosphodiesterase 6

Effect of Knocking Down the Insulin Receptor on Mouse Rod Responses

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