Reaction scheme and model for the generation of photocurrent in human cones. A. Photopigment R is converted by light I into activated photopigment R*, which is inactivated with rate constant 1/τR. R* activates a G-protein (transducin) which subsequently forms an activated complex with PDE. The activated transducin-PDE complex is inactivated with rate constant 1/τE; it hydrolyses cGMP with rate constant β. CNG channels in the membrane, opened under control of cGMP, admit an ionic current Ichan, part of which is carried by Ca2+ ions. Ca2+, which is removed with rate constant 1/τCa, regulates the production rate α of cGMP via guanylyl cyclase (GC). Ca2+ also exerts a direct inhibitory influence on the CNG channels. Part of the ionic current Ichan charges the membrane of the cone outer segment (with membrane time constant τm), and the remainder of Ichan flows into the cone inner segment. In the intact eye the extracellular flow of this circulating current produces an extracellular voltage drop, which is measured as the cone contribution to the ERG (as in Fig. 2). In single-cell experiments the extracellular flow of current may be measured using a suction pipette (as in Fig. 3). B. The boxes with τ(·) represent first-order low-pass filters. The rate constant of cGMP hydrolysis consists of a dark rate constant, 1/τD, plus a light-dependent component with scaling determined by the gain factor kβ. The nonlinear differential equation describing cGMP hydrolysis can be understood as a static nonlinearity 1/β followed by a low-pass filter with time constant τβ = 1/β . The calcium feedback loop is governed by nX, the apparent Hill coefficient of cGMP activation of the CNG channels (including the effect of a local calcium feedback, indicated by the dashed line), and by ncyc, the Hill coefficient of GC deactivation; acyc is a scaling constant.