Figure 9.

The putative role of RD3 in preventing two different types of rapid photoreceptor degeneration.A, in normal photoreceptors, RD3 plays a dual role: (i) it facilitates RetGC delivery to the outer segment and (ii) protects the cells against aberrant activation of guanylyl cyclase in the inner segment until the enzyme reaches its destination in the outer segment, where GCAPs displace RD3 and control RetGC activity via Ca²⁺ feedback. B, in RD3-deficient photoreceptors such as in rd3 mice and LCA12 patients, the RetGC content sharply declines and the production of cGMP in the outer segment becomes insufficient to maintain the normal inward current through CNG channels, which reduces responses to light and possibly provokes a slow component of the degenerative process. The remaining RetGC is no longer protected against aberrant activation by GCAPs, and such activation causes rapid degeneration of the RD3-deficient photoreceptors. C, in photoreceptors expressing GUCY2D dominant gain-of-function mutations (RetGC1^∗), such as CORD6-linked mutation R838S, the higher affinity of the RetGC1^∗ for GCAP causes a “phototransduction disease” by deregulating the suppression of the RetGC1∗ activity by Ca²⁺ in the outer segment, which in turn causes excessive cGMP production and abnormal elevation of Ca²⁺ influx in the dark, promoting the apoptotic process. The increased affinity of RetGC1^∗ for GCAP also hinders RetGC1^∗ silencing by RD3. The aberrant stimulation of the cyclase, possibly in the inner segment, activates the secondary pathway of degeneration, similarly to that in RD3-deficient photoreceptors. D, the increase of RD3 levels by overexpressing RD3GFP enables RD3 to compete with GCAPs for RetGC1^∗ more effectively and offsets the secondary, RD3-related, pathway of the apoptosis. Therefore, the dominant photoreceptor degeneration driven now only by the primary apoptotic pathway of deregulated Ca²⁺ feedback in R838S⁺ outer segment becomes slower. CNG, cyclic nucleotide–gated; CORD6, cone–rod dystrophy 6; GCAP, guanylyl cyclase–activating protein; RD3, retinal degeneration-3 protein; RetGC, the retinal membrane guanylyl cyclase.