title: The B3 Subunit of the Cone Cyclic Nucleotide-gated Channel Regulates the Light Responses of Cones and Contributes to the Channel Structural Flexibility.
abstract: 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.
authors.affiliation: From the Departments of Cell Biology and xi-qin-ding@ouhsc.edu.
authors.forename: Xi-Qin
authors.initials: XQ
authors.lastname: Ding
authors.affiliation: From the Departments of Cell Biology and.
authors.forename: Arjun
authors.initials: A
authors.lastname: Thapa
authors.affiliation: From the Departments of Cell Biology and.
authors.forename: Hongwei
authors.initials: H
authors.lastname: Ma
authors.affiliation: From the Departments of Cell Biology and.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Xu
authors.affiliation: Ophthalmology and Dean McGee Eye Institute, Oklahoma City, Oklahoma 73104.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Elliott
authors.affiliation: Biochemistry, University of Oklahoma Health Sciences Center and.
authors.forename: Karla K
authors.initials: KK
authors.lastname: Rodgers
authors.affiliation: Department of Vision Sciences, University of Alabama, Birmingham, Alabama 35924, and.
authors.forename: Marci L
authors.initials: ML
authors.lastname: Smith
authors.affiliation: Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, Saint Louis, Missouri 63110.
authors.forename: Jin-Shan
authors.initials: JS
authors.lastname: Wang
authors.affiliation: Department of Vision Sciences, University of Alabama, Birmingham, Alabama 35924, and.
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Pittler
authors.affiliation: Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, Saint Louis, Missouri 63110.
authors.forename: Vladimir J
authors.initials: VJ
authors.lastname: Kefalov
mesh_terms: D000818:Animals; D054815:Cyclic Nucleotide-Gated Cation Channels / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008027:Light; D051379:Mice; D018345:Mice, Knockout; D055355:Opsins / Q000235:genetics / Q000378:metabolism; D017949:Retinal Cone Photoreceptor Cells / Q000166:cytology / Q000378:metabolism*
chemical_list: C532622:CNGB3 protein, mouse; C518237:Cnga3 protein, mouse; D054815:Cyclic Nucleotide-Gated Cation Channels; D055355:Opsins
keywords: achromatopsia; cng channel; cone; ion channel; photoreceptor; phototransduction; retina; vision