Molecular and Cellular Biochemistry

, Volume 334, Issue 1–2, pp 125–139 | Cite as

Involvement of rhodopsin and ATP in the activation of membranous guanylate cyclase in retinal photoreceptor outer segments (ROS-GC) by GC-activating proteins (GCAPs): a new model for ROS-GC activation and its link to retinal diseases

  • Vladimir A. Bondarenko
  • Fumio Hayashi
  • Jiro Usukura
  • Akio Yamazaki


Membranous guanylate cyclase in retinal photoreceptor outer segments (ROS-GC), a key enzyme for the recovery of photoreceptors to the dark state, has a topology identical to and cytoplasmic domains homologous to those of peptide-regulated GCs. However, under the prevailing concept, its activation mechanism is significantly different from those of peptide-regulated GCs: GC-activating proteins (GCAPs) function as the sole activator of ROS-GC in a Ca2+-sensitive manner, and neither reception of an outside signal by the extracellular domain (ECD) nor ATP binding to the kinase homology domain (KHD) is required for its activation. We have recently shown that ATP pre-binding to the KHD in ROS-GC drastically enhances its GCAP-stimulated activity, and that rhodopsin illumination, as the outside signal, is required for the ATP pre-binding. These results indicate that illuminated rhodopsin is involved in ROS-GC activation in two ways: to initiate ATP binding to ROS-GC for preparation of its activation and to reduce [Ca2+] through activation of cGMP phosphodiesterase. These two signal pathways are activated in a parallel and proportional manner and finally converge for strong activation of ROS-GC by Ca2+-free GCAPs. These results also suggest that the ECD receives the signal for ATP binding from illuminated rhodopsin. The ECD is projected into the intradiscal space, i.e., an intradiscal domain(s) of rhodopsin is also involved in the signal transfer. Many retinal disease-linked mutations are found in these intradiscal domains; however, their consequences are often unclear. This model will also provide novel insights into causal relationship between these mutations and certain retinal diseases.


Retinal photoreceptor membrane guanylate cyclase Rhodopsin ATP-binding protein GCAPs Retinitis pigmentosa Leber’s congenital amaurosis 



We thank Drs. H. Imai and Y. Shichida (Kyoto University, Kyoto, Japan) for their suggestions of the conformational change of the loop E-II by illumination. We also thank Dr. Ari Sitaramayya (Oakland University, Rochester, Michigan) for his constructive suggestions on measurement of rhodopsin concentration and for providing Ammonyx Lo. We are also indebted to Dr. Naoka Komori (The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma) for the critical reading of the manuscript. This study was supported in part by National Institute of Health Grant EY09631 and an unrestricted grant from Research to Prevent Blindness.


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Copyright information

© Springer Science+Business Media, LLC. 2009

Authors and Affiliations

  • Vladimir A. Bondarenko
    • 1
  • Fumio Hayashi
    • 2
  • Jiro Usukura
    • 3
  • Akio Yamazaki
    • 4
    • 5
    • 6
  1. 1.College of Osteopathic MedicineTouro UniversityHendersonUSA
  2. 2.Department of Biology, Graduate School of ScienceKobe UniversityKobeJapan
  3. 3.Division of Integrated Project, EcoTopia Science InstituteNagoya UniversityNagoyaJapan
  4. 4.Department of OphthalmologyWayne State University, School of MedicineDetroitUSA
  5. 5.Department of PharmacologyWayne State University, School of MedicineDetroitUSA
  6. 6.Kresge Eye InstituteWayne State University, School of MedicineDetroitUSA

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