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S.C. Nicholas, R.D. Hamer; Changes in the Period of Photocurrent Saturation Can Provide Erroneous Estimates of True Underlying Changes in Early Phototransduction Gain: A Theoretical Analysis . Invest. Ophthalmol. Vis. Sci. 2006;47(13):3744.
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© ARVO (1962-2015); The Authors (2016-present)
Changes in the period of saturation following a bright flash (Tsat) have been used to estimate gain changes in the early phototransduction cascade. We demonstrate by simulation, and quantify analytically, discrepancies between empirical estimates and 'true' underlying gain changes and delineate the conditions that lead to these errors.
The theoretical relationship between Tsat and flash intensity is derived from a model of the early cascade, describing the PDE* response to arbitrary R* activity signals. Changes in the R* activity response to a flash (induced by light–adaptation (LA), genetic manipulations, etc.) can thus be transformed into predicted changes in Tsat and gain. Tsat predictions are checked against simulated responses using a model of the full transduction cascade. Gain changes extracted from Tsat are compared with changes in the true gain, i.e., the average integrated R* activity per photon.
Changes in R* inactivation kinetics can lead to either over– or underestimation of underlying gain changes using the Tsat measure. Speeding up the relative rate of R* inactivation will generally lead to overestimates of gain change, and vice versa. The magnitude of these errors may be large when the time scale of R* inactivation is similar to that of PDE*. Additional independent and multiplicative sources of error are introduced in LA paradigms where the adapting light contributes residual R* and/or PDE* activity to the flash response. The polarity of these errors is always towards underestimation of gain changes.
Our analyses reveal that interpretation of changes in Tsat is not straightforward. A quantitative framework is presented with the aim of improving gain change estimates from Tsat data. The expressions derived here permit a priori evaluation of LA experimental designs, and judicious choice of stimulus parameters so as to minimize errors in estimating gain change. For example, we show that some paradigms (e.g., 2–flash , Murnick & Lamb, J Physiol 495: 1, 1996) are inherently less susceptible to errors than others (e.g., step–flash , Fain et al., J Physiol 416:215, 1989). Genetic techniques now permit the kinetics of isolated steps in the early cascade to be selectively altered. Such manipulations may either amplify or diminish errors in gain change estimation. It is thus all the more important to understand how such manipulations might impact on the use of Tsat to estimate underlying phototransduction gain and kinetics.
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