TY - JOUR
T1 - Night blindness and the mechanism of constitutive signaling of mutant G90D rhodopsin
AU - Dizhoor, Alexander M.
AU - Woodruff, Michael L.
AU - Olshevskaya, Elena V.
AU - Cilluffo, Marianne C.
AU - Cornwall, M. Carter
AU - Sieving, Paul A.
AU - Fain, Gordon L.
PY - 2008/11/5
Y1 - 2008/11/5
N2 - 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.
AB - 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.
KW - Adaptation
KW - Photoreceptor
KW - Rhodopsin
KW - Rod
KW - Transduction
KW - Vision
UR - http://www.scopus.com/inward/record.url?scp=58149267461&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=58149267461&partnerID=8YFLogxK
U2 - 10.1523/JNEUROSCI.4006-08.2008
DO - 10.1523/JNEUROSCI.4006-08.2008
M3 - Article
C2 - 18987202
AN - SCOPUS:58149267461
VL - 28
SP - 11662
EP - 11672
JO - Journal of Neuroscience
JF - Journal of Neuroscience
SN - 0270-6474
IS - 45
ER -