A step-by-step model of phototransduction cascade shows that Ca2+ regulation of guanylate cyclase accounts only for short-term changes of photoresponse

Abstract

A mathematical model of the vertebrate phototransduction mechanism was designed in a modular fashion, in that increasingly complex behaviors can be turned on and off to evaluate the relative involvement of all elements of the phototransduction cascade. The problem was approached by starting with a minimum model in which the intracellular cGMP concentration ([cGMP]_i) was determined by guanylate cyclase (GC), whose activity was assumed not to be regulated by any factor (such as Ca²⁺) and by phosphodiesterase (PDE), whose activity was assumed to be proportional to the light intensity. All dependences were subsequently introduced, i.e. the equations describing PDE activation in detail, the Ca²⁺ regulation of GC and the action of intracellular Ca²⁺ buffers. The simulations and fits show that a high-gain, smooth time- and light-dependent PDE activation, a Ca²⁺-dependent GC, and a Ca²⁺-dependent buffer mechanism are required to account for the flash response kinetics in the dark and on dim backgrounds of light, and the effect of exogenous Ca²⁺ buffers to produce responses characterized by slow and damped oscillations and to enhance the low-frequency noise. However, it was not possible to find any set of parameters able to simultaneously interpolate the waveform of the flash responses (in the dark and on a background of light) and the responses to steps of light. It is therefore concluded that at least one more shut-off mechanism (possibly not Ca-dependent) is necessary to fully account for the phenomenology of the light response in rod photoreceptors.