title: Abnormal activation and inactivation mechanisms of rod transduction in patients with autosomal dominant retinitis pigmentosa and the pro-23-his mutation.
abstract: OBJECTIVE
  The leading edge of the rod a-wave in normal human subjects can be fit with a computational model of the activation phase of transduction to provide parameters analogous to those obtained from individual photoreceptors. The authors extend this work to the kinetics of recovery after saturating flashes.
  
  
  METHODS
  Electroretinograms were recorded from three patients with autosomal dominant retinitis pigmentosa and the pro-23-his rhodopsin mutation, two patients with rod monochromatism, and five normal subjects. Rod-only a-waves were obtained for a series of flashes ranging from 4.4 to 10.1 ln (1.9 to 4.4 log) scot td-sec. One set of parameters describing the activation process was derived from fits to the a-wave model. A double-flash paradigm was used to study inactivation mechanisms. The first flash was achromatic and varied in intensity (I(f)) from 6.1 to 13.9 ln (2.6 to 6.0 log) scot td-sec. The second flash was a short-wavelength probe held constant at 9.3 ln (4.0 log) scot td-sec. Cone components were elicited with a photopically matched long-wavelength stimulus and were computer subtracted. Recovery at each I(f) was followed by measuring the amplitude to the probe flash at various interstimulus intervals (ISI). The critical time (Tc) before the initiation of rod recovery was determined from the function relating relative rod amplitude to ISI.
  
  
  RESULTS
  Recovery from activation was similar in normal subjects and in patients with rod monochromatism. Over a large range of I(f) above rod saturation, Tc increased in proportion to ln I(f). The mean slope of the function relating Tc to I(f) was 2.3 s/ln I(f) when I(f) varied between 11 and 13.9 ln scot td-sec. Patients with retinitis pigmentosa and the pro-23-his rhodopsin mutation had a decrease in the gain of activation. They also had significantly slower than normal recovery after high test flash intensities, such that the slope of the function relating Tc to ln I(f) was 12.1 seconds.
  
  
  CONCLUSIONS
  Available data from other species imply that complete, transient activation of transducin (T saturation) occurs within or below the investigated range of flash intensities. Based on the slope of the delay function (delta Tc/ delta ln I(f)) above 11 ln scot td-sec, the authors hypothesize that the lifetime of activated rhodopsin (R) in normal human rods is approximately 2.3 seconds. In patients with the pro-23-his mutation, the gain of the activation mechanism is reduced and the reaction determining the delta Tc/ delta ln I(f) slope is markedly slowed. The activated species that exhibits this prolonged lifetime could be the mutant rhodopsin itself.
authors.affiliation: Retina Foundation of the Southwest, Dallas, TX 75231, USA.
authors.forename: D G
authors.initials: DG
authors.lastname: Birch
authors.forename: D C
authors.initials: DC
authors.lastname: Hood
authors.forename: S
authors.initials: S
authors.lastname: Nusinowitz
authors.forename: D R
authors.initials: DR
authors.lastname: Pepperberg
mesh_terms: D000293:Adolescent; D000328:Adult; D003623:Dark Adaptation; D004596:Electroretinography; D005260:Female; D006639:Histidine; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010775:Photic Stimulation; D011392:Proline; D017949:Retinal Cone Photoreceptor Cells / Q000502:physiology; D017948:Retinal Rod Photoreceptor Cells / Q000502:physiology*; D012174:Retinitis Pigmentosa / Q000235:genetics / Q000503:physiopathology*; D012243:Rhodopsin / Q000737:chemistry / Q000235:genetics*; D015398:Signal Transduction / Q000502:physiology*; D013329:Structure-Activity Relationship
chemical_list: D006639:Histidine; D012243:Rhodopsin; D011392:Proline