CO2/bicarbonate modulates cone photoreceptor ROS-GC1 and restores its CORD6-linked catalytic activity
This study with recombinant reconstituted system mimicking the cellular conditions of the native cones documents that photoreceptor ROS-GC1 is modulated by gaseous CO2. Mechanistically, CO2 is sensed by carbonic anhydrase (CAII), generates bicarbonate that, in turn, directly targets the core catalytic domain of ROS-GC1, and activates it to increased synthesis of cyclic GMP. This, then, functions as a second messenger for the cone phototransduction. The study demonstrates that, in contrast to the Ca2+-modulated phototransduction, the CO2 pathway is Ca2+-independent, yet is linked with it and synergizes it. It, through R787C mutation in the third heptad of the signal helix domain of ROS-GC1, affects cone-rod dystrophy, CORD6. CORD6 is caused firstly by lowered basal and GCAP1-dependent ROS-GC1 activity and secondly, by a shift in Ca2+ sensitivity of the ROS-GC1/GCAP1 complex that remains active in darkness. Remarkably, the first but not the second defect disappears with bicarbonate thus explaining the basis for CORD6 pathological severity. Because cones, but not rods, express CAII, the excessive synthesis of cyclic GMP would be most acute in cones.
KeywordsMembrane guanylate cyclase CO2 Ca2+-sensor GCAP1 Phototransduction Cone-rod dystrophy
We thank Dr. Clint Makino, Boston University, for critical review and constructive comments. This work was supported by National Institutes of Health: EY 023980. The authors are solely responsible for the contents of this study, which may not represent the views of the National Institutes of Health and Human Services. There is no mention of trade names, commercial products, of organizations implying endorsement by the US government.
Compliance with ethical standards
Conflict of interest
The authors declare that they do not have any conflict of interest.
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