Figure 1.

Phototransduction proteins involved in cGMP m2etabolism in health and disease. (A) In darkness, [cGMP] is determined by the basal activities of phosphodiesterase (PDE6) and retinal guanylyl cyclases (GC). PDE6 activity is stimulated when light-activated transducin removes the inhibitory PDE6γ subunit from the catalytic PDE6αβ subunits. Degradation of cGMP causes the cGMP-gated channels to close, preventing Na⁺ and Ca²⁺ influx and lowering [Ca²⁺] due to its continued extrusion by NCKX1. GC activity is Ca²⁺-sensitive through its interaction with Ca²⁺-binding proteins, guanylyl cyclase activating proteins 1 and 2 (GCAP). In darkness, Ca²⁺ enters the cell through open cGMP-gated channels. Under high [Ca²⁺], Ca²⁺-bound GCAP inhibits basal GC activity. When [Ca²⁺] in the outer segment falls following light exposure, GCAP becomes Mg²⁺-bound and stimulates GC to synthesize cGMP. (B) Dominant mutations in GCAPs that activate GC or loss-of-function mutations in PDE6 lead to elevated [cGMP], which in turn can cause excessive Ca²⁺ influx through the open CNG channels or stimulation of PRKG activity, leading to cell death.