Identification of key factors that reduce the variability of the single photon response

Rod photoreceptors mediate vision in dim light. Their biological function is to discriminate between distinct, very low levels of illumination, i.e., they serve as reliable photon counters. This role requires high reproducibility of the response to a particular number of photons. Indeed, single photon responses demonstrate unexpected low variability, despite the stochastic nature of the individual steps in the transduction cascade. We analyzed individual system mechanisms to identify their contribution to variability suppression. These include: (i) cooperativity of the regulation of the second messengers; (ii) diffusion of cGMP and Ca(2+) in the cytoplasm; and (iii) the effect of highly localized cGMP hydrolysis by activated phosphodiesterase resulting in local saturation. We find that (i) the nonlinear relationships between second messengers and current at the plasma membrane, and the cGMP hydrolysis saturation effects, play a major role in stabilizing the system; (ii) the presence of a physical space where the second messengers move by Brownian motion contributes to stabilization of the photoresponse; and (iii) keeping Ca(2+) at its dark level has only a minor effect on the variability of the system. The effects of diffusion, nonlinearity, and saturation synergize in reducing variability, supporting the notion that the observed high fidelity of the photoresponse is the result of global system function of phototransduction.