Control of the guanylate cyclase signaling unit in phototransduction by the RD3 protein

• Applicant: Professor Dr. Karl-Wilhelm Koch
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells ; Biochemistry
• Term: from 2010 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 190739534

Rod and cone photoreceptor cells operate by a fine-balanced homeostasis of two intracellular second messengers, guanosine-3´,5´-cyclic monophosphate (cyclic GMP) and calcium. Cyclic GMP is synthesized by a membrane bound guanylate cyclase and dysregulation of cyclic GMP signaling can cause degeneration of photoreceptor cells. Several forms of hereditary retinal dystrophies like Leber congenital amaurosis, cone-rod dystrophies and retinitis pigmentosa correlate with mutations in the genes of guanylate cyclase and its regulatory proteins named GCAPs. Recent evidence suggests that a protein named RD3 has a crucial role in maintaining photoreceptor function by controlling one of its key signaling units, the guanylate cyclase/ GCAP complex. The aim of the present project is to investigate how the RD3 protein interacts with dystrophy relevant mutants of guanylate cyclase, whether it stabilizes structurally labile forms of some of these mutants, and how it controls their trafficking out of the endoplasmic reticulum. Furthermore, it is planned to investigate how constitutively active mutants of the guanylate cyclase activator GCAP1, which cause cone dystrophies, are influenced by co-expression of and association with the RD3 protein. Finally, the molecular and protein-chemical properties of the RD3 protein itself are not well understood and the project will further focus on structure-function relationships of RD3 and RD3 mutants. Within this framework we will also test the hypothesis, whether a posttranslational modification like phosphorylation of RD3 controls the direct interaction with the cyclic GMP signaling unit. We expect from our studies a deeper understanding of the molecular mechanisms leading to retinal degeneration involving the RD3 protein and its mutual dependencies with the guanylate cyclase complex.

• DFG Programme: Research Grants
• International Connection: Italy
• Participating Person: Dr. Daniele Dell´Orco