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Molecular Mechanisms of Dark Noise in Retinal Cones

David Holcman and Juan I. Korenbrot

Keck Center for Theoretical Neurobiology and Department of Physiology, School of Medicine, University of California at San Francisco, San Francisco, CA 94143

Correspondence to Juan I. Korenbrot: juan{at}itsa.ucsf.edu

Detection threshold in cone photoreceptors requires the simultaneous absorption of several photons because single photon photocurrent is small in amplitude and does not exceed intrinsic fluctuations in the outer segment dark current (dark noise). To understand the mechanisms that limit light sensitivity, we characterized the molecular origin of dark noise in intact, isolated bass single cones. Dark noise is caused by continuous fluctuations in the cytoplasmic concentrations of both cGMP and Ca²⁺ that arise from the activity in darkness of both guanylate cyclase (GC), the enzyme that synthesizes cGMP, and phosphodiesterase (PDE), the enzyme that hydrolyzes it. In cones loaded with high concentration Ca²⁺ buffering agents, we demonstrate that variation in cGMP levels arise from fluctuations in the mean PDE enzymatic activity. The rates of PDE activation and inactivation determine the quantitative characteristics of the dark noise power density spectrum. We developed a mathematical model based on the dynamics of PDE activity that accurately predicts this power spectrum. Analysis of the experimental data with the theoretical model allows us to determine the rates of PDE activation and deactivation in the intact photoreceptor. In fish cones, the mean lifetime of active PDE at room temperature is 55 ms. In nonmammalian rods, in contrast, active PDE lifetime is 555 ms. This remarkable difference helps explain why cones are noisier than rods and why cone photocurrents are smaller in peak amplitude and faster in time course than those in rods. Both these features make cones less light sensitive than rods.

Key Words: phototransduction • phosphodiesterase • guanylate cyclase • cGMP • calcium

Abbreviations used in this paper: GC, guanylate cyclase; CNG, cGMP-gated; PDE, phosphodiesterase; VP, visual pigment.

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