Light adaptation of photoreceptor cells is mediated by Ca-dependent mechanisms. In darkness, Cainflux through cGMP-gated channels into the outer segment of photoreceptors is balanced by Caextrusion via Na/Ca, Kexchangers (NCKXs). Light activates a G protein signaling cascade, which closes cGMP-gated channels and decreases Calevels in photoreceptor outer segment because of continuing Caextrusion by NCKXs. Guanylate cyclase-activating proteins (GCAPs) then up-regulate cGMP synthesis by activating retinal membrane guanylate cyclases (RetGCs) in low CaThis activation of RetGC accelerates photoresponse recovery and critically contributes to light adaptation of the nighttime rod and daytime cone photoreceptors. In mouse rod photoreceptors, GCAP1 and GCAP2 both contribute to the Ca-feedback mechanism. In contrast, only GCAP1 appears to modulate RetGC activity in mouse cones because evidence of GCAP2 expression in cones is lacking. Surprisingly, we found that GCAP2 is expressed in cones and can regulate light sensitivity and response kinetics as well as light adaptation of GCAP1-deficient mouse cones. Furthermore, we show that GCAP2 promotes cGMP synthesis and cGMP-gated channel opening in mouse cones exposed to low CaOur biochemical model and experiments indicate that GCAP2 significantly contributes to the activation of RetGC1 at low Cawhen GCAP1 is not present. Of note, in WT mouse cones, GCAP1 dominates the regulation of cGMP synthesis. We conclude that, under normal physiological conditions, GCAP1 dominates the regulation of cGMP synthesis in mouse cones, but if its function becomes compromised, GCAP2 contributes to the regulation of phototransduction and light adaptation of cones. 2+ 2+ 2+ + 2+ + 2+ 2+ 2+ 2+ 2+ 2+
