title: Cone deactivation kinetics and GRK1/GRK7 expression in enhanced S cone syndrome caused by mutations in NR2E3.
abstract: OBJECTIVE
  To determine the relationship between cone deactivation kinetics in patients with the enhanced S cone syndrome (ESCS) caused by mutations in NR2E3 and the immunoreactivity to G-protein-coupled receptor kinase 1 (GRK1) and GRK7.
  
  
  METHODS
  Electroretinogram (ERG) photoresponses were used to investigate activation kinetics of cones with a model of cone phototransduction. Deactivation kinetics of cones after bright flashes was quantified with a paired-flash ERG paradigm. Immunocytochemistry was performed with antibodies against cone opsins and kinases GRK1 and GRK7 in postmortem normal and ESCS retinal tissue.
  
  
  RESULTS
  Activation kinetics of long/middle-wavelength-sensitive (L/M) cone-mediated responses in patients with ESCS were similar to those of normal L/M cones. Activation kinetics of ESCS short-wavelength-sensitive (S) cones, when compared with normal L/M cone responses evoked by the same stimulus, were slower by an amount consistent with the expected differences in spectral sensitivities. After bright flashes chosen to evoke identical activation kinetics, ESCS S cones deactivated much more slowly than ESCS or normal L/M cones. Normal human retina revealed strongly labeled cone outer segments with anti-GRK1 and anti-GRK7. In an ESCS retina, outer segments positive for L/M opsin were strongly labeled with anti-GRK1, whereas outer segments positive for S opsin showed no detectable GRK1 reactivity. GRK7 labeling was absent in all photoreceptors of the ESCS retina.
  
  
  CONCLUSIONS
  The cone-dominant human retina resulting from NR2E3 mutations affords greater understanding of the physiological roles of GRK1 and GRK7 in human cone photoreceptors. Normal deactivation kinetics in human L/M cones can occur without GRK7 when GRK1 is present in ESCS, but does not occur when GRK7 is present but GRK1 is deficient in Oguchi disease. Lack of both GRK1 and GRK7 in S cones of patients with ESCS results in a more pronounced abnormality in deactivation kinetics and suggests the existence of partial compensation by either GRK when the other is deficient.
authors.affiliation: Department of Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. cideciya@mail.med.upenn.edu
authors.forename: Artur V
authors.initials: AV
authors.lastname: Cideciyan
authors.forename: Samuel G
authors.initials: SG
authors.lastname: Jacobson
authors.forename: Nisha
authors.initials: N
authors.lastname: Gupta
authors.forename: Shoji
authors.initials: S
authors.lastname: Osawa
authors.forename: Kristin G
authors.initials: KG
authors.lastname: Locke
authors.forename: Ellen R
authors.initials: ER
authors.lastname: Weiss
authors.forename: Alan F
authors.initials: AF
authors.lastname: Wright
authors.forename: David G
authors.initials: DG
authors.lastname: Birch
authors.forename: Ann H
authors.initials: AH
authors.lastname: Milam
mesh_terms: D004596:Electroretinography; D005136:Eye Proteins / Q000378:metabolism; D019084:Fluorescent Antibody Technique, Indirect; D051606:G-Protein-Coupled Receptor Kinase 1; D054768:G-Protein-Coupled Receptor Kinases; D006801:Humans; D007700:Kinetics; D009154:Mutation; D057093:Orphan Nuclear Receptors; D010775:Photic Stimulation; D011494:Protein Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics*; D017949:Retinal Cone Photoreceptor Cells / Q000201:enzymology*; D012162:Retinal Degeneration / Q000201:enzymology* / Q000235:genetics*; D017299:Rod Opsins / Q000378:metabolism; D013577:Syndrome; D014157:Transcription Factors / Q000235:genetics*; D014785:Vision, Ocular
chemical_list: D005136:Eye Proteins; C403073:NR2E3 protein, human; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D017299:Rod Opsins; D014157:Transcription Factors; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D051606:G-Protein-Coupled Receptor Kinase 1; C496764:GRK1 protein, human; C111571:GRK7 protein, human; D054768:G-Protein-Coupled Receptor Kinases