Analysis of Ca++-dependent gain changes in PDE activation in vertebrate rod phototransduction

• Published in: Molecular vision 2000-12, Vol.6, p.265-286
• Main Author: Hamer, R D
• Format: Article
• Language: English
• Subjects: 3',5'-Cyclic-GMP Phosphodiesterases - metabolism; Animals; Bufonidae; Calcium - physiology; Calcium Channels - metabolism; Computational Biology; Dark Adaptation; Electrophysiology; Enzyme Activation; Hydrolysis; Mathematics; Models, Biological; Photic Stimulation; Photoreceptor Cells, Vertebrate - physiology; Retinal Rod Photoreceptor Cells - physiology; Salamandridae; Vision, Ocular - physiology
• ISSN: 1090-0535

Recent biochemical and physiological data point to the existence of one or more Ca++-mediated feedback mechanisms modulating gain at stages early in the vertebrate phototransduction cascade, i.e., prior to activation of cGMP-phosphodiesterase (PDE). The present study is a computational analysis that combines quantitative optimization to key data with a qualitative evaluation of each candidate model's ability to capture "signature" features of representative rod responses obtained under a broad range of dark- (DA) and light-adapted (LA) conditions. The primary data motivating the analyses were the two-flash data of Murnick & Lamb. These data exhibited strikingly nonlinear behavior: the period of complete photocurrent saturation (Tsat) in response to a Test flash was reduced substantially when preceded by a less-intense saturating Pre-flash. Depending on the delay between Pre- and Test flashes, the change in Tsat (DTsat) could exceed the magnitude of the delay, and could be reduced by as much as approximately 50%, corresponding to a large reduction in gain by a factor of 10-15. The overall goal of the study was to evaluate what model structure(s) were commensurate with both the Murnick & Lamb data and the salient qualitative features of rod responses obtained under a broad range of DA and LA conditions. Three candidate models were quantitatively optimized to the Murnick & Lamb saturated toad rod flash responses and, simultaneously, to a set of sub-saturated flash responses. Using the parameters from these optimizations, each candidate model was then used to simulate a suite of DA and LA responses. The analyses showed that: (1) Within the context of a model with Ca++ feedback onto rhodopsin (R*) lifetime (tR), the salient features of the Murnick & Lamb data can only be accounted for if the rate-limiting step is not the Ca++-sensitive step in the early cascade reactions, i.e., if PDE* lifetime, and not tR, is rate-limiting. (2) With tR rate-limiting, the model cannot account for DTsat exceeding the delay. (3) The Ca++-dependent reduction in tR required to effect the large gain is incommensurate with the empirical dynamics of dim-flash responses. (4) Regardless of which reaction is rate-limiting, a model using solely modulation of R* lifetime puts strong constraints on the domain of biochemical parameters commensurate with the large gain changes Murnick & Lamb observed. (5) The analyses show that, in principle, the Murnick & Lamb data can be accounted for when