Following light exposure, photoreceptors in the vertebrate neural retina re-establish a dark-adapted state. A critical step in this process is the intracellular stimulation of the enzyme guanylate cyclase (GC). GC-activating proteins (GCAP1, GCAP2 and GCAP3) modulate GC activation. GCAP activation of GC is regulated by the intracellular calcium ion concentration [Ca2+]i. In photoreceptors bleached by light, [Ca2+]i decreases, causing GCAP1 to stimulate GC. As [Ca2+]i increases during dark adaptation, GCAP1 is inactivated. Previous studies have localized GCAP1 to rod and cone outer segments, somata and synaptic terminals. Mutations in GCAP1 cause an autosomal dominant form of cone photoreceptor dystrophy in humans. We have found that this mutant form of GCAP1, (Y99C), exhibits altered sensitivity to [Ca2+]i, resulting in persistent stimulation of GC in dark conditions. Constitutive activation of GCAP1 may produce elevated levels of cGMP in dark-adapted cones, resulti ng i n the degeneration of these sensory neurons. On-going studies using primate retinal tissues are focused on understanding the enzymatic interactions between GCAPs and GC. FUNDING NIH grants EY09339, EY08061, and RR00166.
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