Mouse models to study GCAP functions in intact photoreceptors

Abstract

In photoreceptor cells cGMP is the second messenger that transduces light into an electrical response. Regulation of cGMP synthesis by Ca2+ is one of the key mechanisms by which Ca2+ exerts negative feedback to the phototransduction cascade in the process of light adaptation. This Ca2+ feedback to retinal guanylyl cyclases (Ret-GCs) is conferred by the guanylate cyclase-activating proteins (GCAPs). Mutations in GCAP1 that disrupt the Ca2+ regulation of Ret-GCs in vitro have been associated with severe human vision disorders. This chapter focuses on recent data obtained from biochemical and electrophysiological studies of GCAP1/GCAP2 knockout mice and other GCAP transgenic mice, addressing: 1. the quantitative aspects of the Ca2+-feedback to Ret-GCs in regulating the light sensitivity and adaptation in intact rods; 2. functional differences between GCAP1 and GCAP2 in intact rod photoreceptors; and 3. whether GCAP mutants with impaired Ca2+ binding lead to retinal disease in vivo by constitutive activation of Ret-GCs and elevation of intracellular cGMP, as predicted from in vitro studies.