Night blindness and the mechanism of constitutive signaling of mutant G90D rhodopsin

Alexander M. Dizhoor, Michael L. Woodruff, Elena V. Olshevskaya, Marianne C. Cilluffo, M. Carter Cornwall, Paul A. Sieving, Gordon L. Fain

Research output: Contribution to journalArticlepeer-review

34 Scopus citations

Abstract

The G90D rhodopsin mutation is known to produce congenital night blindness in humans. This mutation produces a similar condition in mice, because rods of animals heterozygous (D+) or homozygous (D+/+) for this mutation have decreased dark current and sensitivity, reduced Ca2+, and accelerated values of τREC and τD, similar to light-adapted wild-type (WT) rods. Our experiments indicate that G90D pigment activates the cascade, producing an equivalent background light of ∼130 Rh* rod-1 for D+ and 890 Rh* rod-1 for D+/+. The active species of the G90D pigment could be unregenerated G90D opsin or G90D rhodopsin, either spontaneously activated (as Rh*) or in some other form. Addition of 11-cis-retinal in lipid vesicles, which produces regeneration of both WT and G90D opsin in intact rods and ROS membranes, had no effect on the waveform or sensitivity of dark-adapted G90D responses, indicating that the active species is not G90D opsin. The noise spectra of dark-adapted G90D and WT rods are similar, and the G90D noise variance is much less than of a WT rod exposed to background light of about the same intensity as the G90D equivalent light, indicating that Rh* is not the active species. We hypothesize that G90D rhodopsin undergoes spontaneous changes in molecular conformation which activate the transduction cascade with low gain. Our experiments provide the first indication that a mutant form of the rhodopsin molecule bound to its 11-cis-chromophore can stimulate the visual cascade spontaneously at a rate large enough to produce visual dysfunction.

Original languageEnglish (US)
Pages (from-to)11662-11672
Number of pages11
JournalJournal of Neuroscience
Volume28
Issue number45
DOIs
StatePublished - Nov 5 2008
Externally publishedYes

Keywords

  • Adaptation
  • Photoreceptor
  • Rhodopsin
  • Rod
  • Transduction
  • Vision

ASJC Scopus subject areas

  • Neuroscience(all)

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