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

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 Ca(2+), and accelerated values of tau(REC) and tau(D), similar to light-adapted wild-type (WT) rods. Our experiments indicate that G90D pigment activates the cascade, producing an equivalent background light of approximately 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.

• Authors: Alexander M Dizhoor, Michael L Woodruff, Elena V Olshevskaya, Marianne C Cilluffo, M Carter Cornwall, Paul A Sieving, Gordon L Fain
• Journal: The Journal of neuroscience : the official journal of the Society for Neuroscience (J Neurosci) Vol. 28 Issue 45 Pg. 11662-72 (Nov 05 2008) ISSN: 1529-2401 [Electronic] United States
• PMID: 18987202 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)

Chemical References

• Carrier Proteins
• Eye Proteins
• Opsins
• Aspartic Acid
• Rhodopsin
• retinoid isomerohydrolase
• cis-trans-Isomerases
• Retinaldehyde
• Calcium
• Glycine

Topics

• Animals
• Aspartic Acid (genetics)
• Calcium (metabolism)
• Carrier Proteins (genetics)
• Dark Adaptation (genetics)
• Disease Models, Animal
• Dose-Response Relationship, Radiation
• Eye Proteins (genetics)
• Glycine (genetics)
• Kinetics
• Light Signal Transduction (genetics)
• Membrane Potentials (drug effects, genetics)
• Mice
• Mice, Transgenic
• Mutation
• Night Blindness (genetics, physiopathology)
• Opsins (genetics, metabolism)
• Photic Stimulation (methods)
• Retinal Rod Photoreceptor Cells (drug effects, metabolism)
• Retinaldehyde (pharmacology)
• Rhodopsin (genetics)
• Spectrum Analysis
• Time Factors
• cis-trans-Isomerases