Mutations in the rod outer segment membrane guanylate cyclase in a cone- rod dystrophy cause defects in calcium signaling

Teresa Duda, Anuradha Krishnan, Venkateswar Venkataraman, Christian Lange, Karl Wilhelm Koch, Rameshwar K. Sharma

Research output: Contribution to journalArticle

39 Scopus citations

Abstract

Rod outer segment guanylate cyclase 1 (ROS-GC1) is a member of the subfamily of Ca2+-regulated membrane guanylate cyclases; and it is pivotal for vertebrate phototransduction. Two opposing regulatory modes control the activity of ROS-GC1. At nanomolar concentrations of Ca2+, ROS-GC1 is activated by Ca2+-binding proteins named guanylate cyclase activating proteins (GCAPs). However, at micromolar concentrations of Ca2+, ROS-GC1 is stimulated by S100β [also named calcium-dependent (CD) GCAP]. This mode is not linked with phototransduction; instead, it is predicted to be involved in retinal synaptic activity. Two point mutations, E786D and R787C, in ROS-GC1 have been connected with cone-rod dystrophy (CORD6), with only one type of point mutation occurring in each family. The present study shows that the E786D mutation has no effect on the basal catalytic activity of ROS-GC1 and on its activation by GCAP1 and S100β; however, the mutated cyclase becomes more activated by GCAP2. The R787C mutation has three consequences: (1) it causes major damage to the basal cyclase activity, (2) it makes the cyclase 5-fold more sensitive to activation by GCAP1; and 3) converts the cyclase into a form that is less sensitive to activation by GCAP2 and S100β. Thus, the two CORD6-linked mutations in ROS-GC1, which occur at adjacent positions, result in vastly different biochemical phenotypes, and they are connected with very specific molecular defects in the Ca2+ switching components of the cyclase. These defects, in turn, are proposed to have a profound effect on both the machinery of phototransduction and the retinal synapse. The study for the first time defines the biochemistry of CORD6 pathology in precise molecular terms.

Original languageEnglish (US)
Pages (from-to)13912-13919
Number of pages8
JournalBiochemistry
Volume38
Issue number42
DOIs
StatePublished - Oct 19 1999

All Science Journal Classification (ASJC) codes

  • Biochemistry

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