abstract 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 Ca 2 � 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 Ca 2 � 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:

The illumination at the earth’s surface varies by �10 orders of magnitude during the normal day–night cycle, and the vertebrate visual system covers this entire range of light intensities with two neuronal subsystems that rely on the activity of two types of photoreceptor cells, rods and cones. Human rod vision operates over approximately seven decimal orders of illumination. The cone visual system operates over an even wider range (Rodieck, 1998). Light adaptation occurs at all levels of the visual system, from photoreceptors to central neurons. Yet, the function of the entire visual system depends on the ability of the photoreceptors themselves to adjust their sensitivity to the ambient lighting situation. Thus, photoreceptors must generate reliable signals at night when single photons are captured between long intervals of darkness, and must also continue to signal at the very high light intensities encountered on a sunny day. Photoreceptor light adaptation is likely to be mediated by multiple and perhaps redundant molecular mechanisms (Detwiler and Gray-Keller,