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The C-terminal domain of RD3 enables accumulation of retinal membrane guanylyl cyclase (RetGC) in photoreceptor outer segment
Journal article   Open access   Peer reviewed

The C-terminal domain of RD3 enables accumulation of retinal membrane guanylyl cyclase (RetGC) in photoreceptor outer segment

Elena V Olshevskaya, Igor V Peshenko and Alexander M Dizhoor
The Journal of biological chemistry, p113277
22 Jun 2026
DOI: https://doi.org/10.1016/j.jbc.2026.113277
PMID: 42331110
url
https://doi.org/10.1016/j.jbc.2026.113277View
Published, Version of Record (VoR) Open

Abstract

RD3 retinal degeneration cyclic GMP (cGMP) GC-E retina photoreceptor guanylate cyclase (guanylyl cyclase) GCAP calcium binding proteins RetGC Vision Signal Transduction
Retinal degeneration-3 protein (RD3) plays a dual role in photoreceptors - prevents their degeneration by suppressing aberrant activity of retinal membrane guanylyl cyclase (RetGC) in the inner segment and enables photoreceptor function by facilitating delivery of RetGC to the outer segment. Parts of RD3 structure supporting its dual function were evaluated in vivo using deletion mutants of a human RD3 transgenically expressed under the control of rod opsin promoter in Rd3 mouse rods lacking endogenous RD3. The human RD3 truncated after Gly or Arg not only inhibited RetGC activation by the guanylyl cyclase activating protein (GCAP) in vitro but also prevented rapid degeneration of the RD3-deficient rods in transgenic mice. However, these deletion mutants did not restore RetGC trafficking in Rd3 rods to the outer segment or normal rod function. Extending RD3 polypeptide to Ser restored RetGC accumulation in the outer segment of rescued Rd3 rods and enabled their photoresponse. These findings indicate that the RD3 serves as a 'ski lift' for RetGC produced in the inner segment, in which Arg -Ser region of RD3 mediates coupling of the RetGC:RD3 complex to intracellular protein trafficking, while its α-helical core N-terminal to Gly binds RetGC and suppresses its aberrant activation by GCAP in the inner segment in order to prevent degeneration of photoreceptors.

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