The B3 Subunit of the Cone Cyclic Nucleotide-gated Channel Regulates the Light Responses of Cones and Contributes to the Channel Structural Flexibility

• Published in: The Journal of biological chemistry Vol. 291; no. 16; pp. 8721 - 8734
• Main Authors: Ding, Xi-Qin, Thapa, Arjun, Ma, Hongwei, Xu, Jianhua, Elliott, Michael H., Rodgers, Karla K., Smith, Marci L., Wang, Jin-Shan, Pittler, Steven J., Kefalov, Vladimir J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15-04-2016; American Society for Biochemistry and Molecular Biology
• Subjects: achromatopsia; Animals; cng channel; cone; Cyclic Nucleotide-Gated Cation Channels - genetics; Cyclic Nucleotide-Gated Cation Channels - metabolism; Humans; ion channel; Light; Membrane Biology; Mice; Mice, Knockout; Opsins - genetics; Opsins - metabolism; photoreceptor; phototransduction; retina; Retinal Cone Photoreceptor Cells - cytology; Retinal Cone Photoreceptor Cells - metabolism; vision; vision; ion channel; retina; cng channel; photoreceptor; achromatopsia; cone; phototransduction
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M115.696138

Cone photoreceptor cyclic nucleotide-gated (CNG) channels play a pivotal role in cone phototransduction, which is a process essential for daylight vision, color vision, and visual acuity. Mutations in the cone channel subunits CNGA3 and CNGB3 are associated with human cone diseases, including achromatopsia, cone dystrophies, and early onset macular degeneration. Mutations in CNGB3 alone account for 50% of reported cases of achromatopsia. This work investigated the role of CNGB3 in cone light response and cone channel structural stability. As cones comprise only 2–3% of the total photoreceptor population in the wild-type mouse retina, we used Cngb3−/−/Nrl−/− mice with CNGB3 deficiency on a cone-dominant background in our study. We found that, in the absence of CNGB3, CNGA3 was able to travel to the outer segments, co-localize with cone opsin, and form tetrameric complexes. Electroretinogram analyses revealed reduced cone light response amplitude/sensitivity and slower response recovery in Cngb3−/−/Nrl−/− mice compared with Nrl−/− mice. Absence of CNGB3 expression altered the adaptation capacity of cones and severely compromised function in bright light. Biochemical analysis demonstrated that CNGA3 channels lacking CNGB3 were more resilient to proteolysis than CNGA3/CNGB3 channels, suggesting a hindered structural flexibility. Thus, CNGB3 regulates cone light response kinetics and the channel structural flexibility. This work advances our understanding of the biochemical and functional role of CNGB3 in cone photoreceptors.