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A. Navid, R.D. Hamer; A Potential Role for All–Trans Retinal in Regulation of Metarhodopsin Decay in Human Rods . Invest. Ophthalmol. Vis. Sci. 2006;47(13):2038.
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We sought to develop a model that could better account for the full dynamics of human rod pigment regeneration across all bleach levels. Regeneration data have an early fast recovery phase, and a later slow phase (Jaeger et al., Biochem 35: 2901, 1996) that are difficult to account for with current models. One possible cause of this behavior is the interplay between two known pathways of metarhodopsin regeneration, the classical mechanism (CLM) and the channeling mechanism (CHM). CLM assumes that after light exposure, the active (MII) and storage (MIII) metarhodopsin species decay in a slow reaction to free all–trans retinal (tral) and opsin. CHM (Schädel et al., JBC 278: 24896, 2003)suggests that post–bleach tral leaves the rhodopsin (R) "active site" and binds to an "exit site" where it is reduced to trans–retinol (trol) by the enzyme all–trans retinol dehydrogenase (tRDH). trol remains attached to the exit site until a new 11–cis retinal (cral) chromophore attaches to the "entrance site" and initiates trol's dissociation from opsin. In order to examine the relatives roles of CHM and CLM on the overall dynamics of pigment regeneration in human rods, we developed a model of the retinoid cycle that expands on the MLP model (Mahroo & Lamb, JP 554: 417, 2004; Lamb & Pugh, Prog Ret Eye Res 23: 307, 2004).
Karyote software (Ortoleva et al., Omics 7: 269, 2003) was used to simulate the reactions in the MLP model, the reactions for decay of metarhodopsin, and the activity of tRDH leading to formation of trol or opsin–all–trans–retinol (otrol). Data used for parameterization were from Lamb & Pugh (2004) and Rushton & Powell (Vis Res 12: 1073, 1972).
1) Neither CHM nor CLM can, on their own or in any linear combination, adequately account for the dynamics of R regeneration at all bleach levels. 2) The rate of R regeneration via CLM is ∼5 times faster than via CHM, since it is not dependent on the slow tRDH reaction. 3) A regulatory mechanism, whereby tral allosterically activates the channeling mechanism and inhibits the classical mechanism, can accurately account for the data, including the two phases of pigment regeneration.
If tral acts as an end–product inhibitor of CLM and as an allosteric activator of the CHM, our model can account for the full, multiphase dynamics of R regeneration. We thus propose that the retinoid cycle includes a regulated decay of metarhodopsin where both the channeling and classical mechanisms work in tandem, with the early post flash period (2–3 minutes) dominated by the classical mechanism, after which channeling dominates.
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