TY - JOUR
T1 - The B3 subunit of the cone cyclic nucleotide-gated channel regulates the light responses of cones and contributes to the channel structural flexibility
AU - Ding, Xi Qin
AU - Thapa, Arjun
AU - Ma, Hongwei
AU - Xu, Jianhua
AU - Elliott, Michael H.
AU - Rodgers, Karla K.
AU - Smith, Marci L.
AU - Wang, Jin Shan
AU - Pittler, Steven J.
AU - Kefalov, Vladimir J.
N1 - Funding Information:
This work was supported by grants from the National Center for Research Resources (P20RR017703), the National Eye Institute (P30EY021725, T32EY023202, EY019490 (X. Q. D.), EY019494 (M. H. E.), AI-094141 (K. K. R.), EY018143(S. J. P.), EY003039 (S. J. P.), EY019312(V. J. K.), EY021126 (V.J. K.), and EY002687 to the Department of Ophthalmology and Visual Sciences at Washington University), the Research to Prevent Blindness, and the Oklahoma Center for the Advancement of Science and Technology. The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Publisher Copyright:
© 2016 by The American Society for Biochemistry and Molecular Biology, Inc.
PY - 2016/4/15
Y1 - 2016/4/15
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84965021869&partnerID=8YFLogxK
U2 - 10.1074/jbc.M115.696138
DO - 10.1074/jbc.M115.696138
M3 - Article
C2 - 26893377
AN - SCOPUS:84965021869
SN - 0021-9258
VL - 291
SP - 8721
EP - 8734
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 16
ER -