EC Ophthalmology

Retinal photoreceptor degenerative diseases such as rod-cone dystrophies are caused by mutations in retinal Ca²⁺-binding proteins (called GCAPs) that weaken their binding to Ca²⁺ and cause dysregulation of retinal guanylyl cyclase (RetGC). The enzymatic activity of RetGC is activated by its binding to Ca²⁺-free GCAPs in light-adapted photoreceptors, whereas RetGC is inhibited by its binding to Ca²⁺-bound GCAPs in dark-adapted photoreceptors. This Ca²⁺-dependent regulation of cyclase activity is important for coordinating the recovery phase of visual phototransduction. Mutations in GCAP1 (G86R, Y99C, I143N) that weaken its Ca²⁺ binding also cause constitutive activation of RetGC that in turn leads to rod-cone dystrophies. In this mini review, I propose a structural mechanism to explain how GCAPs control the Ca²⁺-dependent activation of RetGC.

 Keywords: Guanylyl Cyclase; Cone-Rod Dystrophy; Retina; Phototransduction; GCAP1; RetGC

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