Channel Modulation and the Mechanism of Light Adaptation in Mouse Rods

Abstract

Vertebrate photoreceptors are thought to adapt to light by a change in Ca2+, which is postulated to mediate modulation of (1) excited rhodopsin (Rh*) by Ca2+-dependent binding of recoverin, (2) guanylyl cyclase activity via Ca2+-dependent GCAP proteins, and (3) cyclic nucleotide-gated channels by binding of Ca2+-calmodulin. Previous experiments genetically deleted recoverin and the GCAPs and showed that significant regulation of sensitivity survives removal of (1) and (2). We genetically deleted the channel Ca2+-calmodulin binding site in the mouseMus musculusand found that removal of (3) alters response waveform, but removal of (3) or of (2) and (3) together still leaves much of adaptation intact. These experiments demonstrate that an important additional mechanism is required, which other experiments indicate may be regulation of phosphodiesterase 6 (PDE6). We therefore constructed a kinetic model in which light produces a Ca2+-mediated decrease in PDE6 decay rate, with the novel feature that both spontaneously activated and light-activated PDE6 are modulated. This model, together with Ca2+-dependent acceleration of guanylyl cyclase, can successfully account for changes in sensitivity and response waveform in background light.