Fig. 12.

Two modes of ROS-GC1 modulation by [Ca²⁺]_i in cones. Dark state (left). At [Ca²⁺]_i = 250 nM Ca²+ sensors: GCAP1, GCAP2, S100B are ROS-GC1 bound; GCAP1 and GCAP2 are [Ca²⁺]_i bound; ROS-GC1 is in the basal state. Cyclic GMP generated keeps a fraction of CNG channels open allowing influx of Na⁺ and Ca²⁺. Hyperpolarization-GCAP mode (Top right). LIGHT triggers activation of phosphodiesterase and hydrolysis of cyclic GMP. The decrease in cyclic GMP causes CNG channels to close, preventing influx of Na⁺ and Ca²⁺ and hyperpolarizing the outer segment plasma membrane. Extrusion of Ca²⁺ by the Na⁺/ Ca²⁺-K⁺ exchanger lowers [Ca²⁺]_i from 250 nM to about 25 nM. The decline causes GCAPs to stimulate ROS-GC1. Depolarization-S100B mode (Bottom right). In the pathological state, [Ca²⁺]_i levels rise above 500 nM. Ca²⁺ is captured by S100B, triggering activation of ROS-GC1. Cyclic GMP formed opens more CNG channels, increasing the influx of Na⁺ and Ca²⁺ and raising [Ca²⁺]_i to even higher levels. Extrusion of Ca²⁺ through Na⁺/Ca²⁺-K⁺ exchanger slows as the ion gradients collapse. The cone outer segment membranes stay in ever-DARK-state.