Abstract
We examine the implications of a recent report providing evidence that two transducins must bind to the rod phosphodiesterase to elicit significant hydrolytic activity. To predict the rod photoreceptor's electrical response, we use numerical simulation of the two-dimensional diffusional contact of interacting molecules at the surface of the disc membrane, and then we use the simulated PDE activity as the driving function for the downstream reaction cascade. The results account for a number of aspects of rod phototransduction that have previously been puzzling. For example, they explain the existence of a greater initial delay in rods than in cones. Furthermore, our analysis suggests that the ‘continuous’ noise recorded in rods in darkness is likely to arise from spontaneous activation of individual molecules of PDE at a rate of a few tens per second per rod, probably as a consequence of spontaneous activation of transducins at a rate of thousands per second per rod. Hence, the dimeric activation of PDE in rods provides immunity against spontaneous transducin activation, thereby reducing the continuous noise. Our analysis also provides a coherent quantitative explanation of the amplification underlying the single photon response. Overall, numerical analysis of the dimeric activation of PDE places rod phototransduction in a new light.
Highlights
Three key proteins mediating activation of the light response in rod photoreceptors are located in the disc membranes of the cell’s outer segment, and comprise rhodopsin, transducin and the PDE
From the analysis of the steady state, we find that 90% of the circulating current is suppressed for a hydrolytic activity of b 1⁄4 66.6 s21, which is produced by about 2700 PDE** in the outer segment
We examine the quantitative consequences that our model and simulations have for a more comprehensive understanding of phototransduction, especially in relation to the single-photon response and the continuous noise
Summary
Three key proteins mediating activation of the light response in rod photoreceptors are located in the disc membranes of the cell’s outer segment, and comprise rhodopsin (a G-protein-coupled receptor), transducin (a heterotrimeric G-protein) and the PDE (a heterotetrameric cyclic GMP phosphodiesterase, PDE6). One major advantage of this arrangement for the rod is that it provides immunity against noise generated by random activation of the PDE triggered by spontaneous thermal activation of G* [3,4,5] This protection is conferred because it is only upon the concerted activation of multiple G*s, catalysed by an isomerized rhodopsin molecule (R*), that there is a sufficiently high local concentration of G* for any given molecule of G* to be able to ‘find’ a singly bound PDE* to bind to, and thereby activate it to PDE**. On the assumption that these PDE** events are triggered by transducin, we estimate the rate of spontaneous activation of transducin molecules to be far higher, at approximately 2500–4500 G* events s21 per rod, with the average response to each transducin activation being far smaller than that induced by each PDE**
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