Progress in Retinal and Eye Research 23 (2004) 307–380
Dark adaptation and the retinoid cycle of vision
T.D. Lamb
a,
*, E.N. Pugh Jr.
b
a
Division of Neuroscience, John Curtin School of Medical Research, Australian National University, Canberra ACT 2601, Australia
b
F.M. Kirby Center for Molecular Ophthalmology, Department of Ophthalmology and Institute of Neurological Sciences, Stellar-Chance Laboratories,
University of Pennsylvania, Philadelphia, PA 19104-6069, USA
Abstract
Following exposure of our eye to very intense illumination, we experience a greatly elevated visual threshold, that takes tens of
minutes to return completely to normal. The slowness of this phenomenon of ‘‘dark adaptation’’ has been studied for many decades,
yet is still not fully understood. Here we review the biochemical and physical processes involved in eliminating the products of light
ARTICLE IN PRESS
2.2.2. General ideas and principles relating to the retinoid cycle . . . . . . . . . . . . . . . . . . 319
2.3. Sub-cellular organization of retinoid processing . . . . . . . . . . . . . . . . . .......... 320
2.3.1. Sub-cellular organization within the RPE cell ........................ 3202.3.2. Molecular organization at the level of the opsin molecule: the opsin cycle . . . . . . . . . 321
*Corresponding author.
E-mail address: trevor.lamb@anu.edu.au (T.D. Lamb).1350-9462/$ - see
doi:10.1016/j.pre2. Anatomy and biochemistry of the retinoid cycle . . . . . . . . . . . . . . . ............... 313
2.1. Anatomy of the photoreceptor–RPE interface . . . . . . . . . . . . . . . . . . .......... 314
2.1.1. Choriocapillaris . . . . . . . . . . . . . . . ........................ 314
2.1.2. Bruch’s membrane . . . . . . . . . . . . . . ........................ 315
2.1.3. The retinal pigment epithelium (RPE) . . . . ........................ 315
2.1.4. The inter-photoreceptor matrix (IPM) . . . . ........................ 315
2.1.5. Photoreceptor outer segments . . . . . . . . ........................ 316
2.2. Retinoid processing cycle: overview . . . . . . . . . . . . . . . . . . . . . . . .......... 316
2.2.1. Summary of the steps comprising the retinoid cycle . . . . . . . . . . . . . . . . . . . . . 316recovery of psychophysical threshold, the recovery of rod photoreceptor circulating current, and the regeneration of rhodopsin. We
begin with normal human subjects, and then analyse the recovery in several retinal disorders, including Oguchi disease, vitamin A
deficiency, fundus albipunctatus, Bothnia dystrophy and Stargardt disease. We review a large body of evidence showing that the time-
course of human dark adaptation and pigment regeneration is determined by the local concentration of 11-cis retinal, and that after
a large bleach the recovery is limited by the rate at which 11-cis retinal is delivered to opsin in the bleached rod outer segments. We
present a mathematical model that successfully describes a wide range of results in human and other mammals. The theoretical
analysis provides a simple means of estimating the relative concentration of free 11-cis retinal in the retina/RPE, in disorders
exhibiting slowed dark adaptation, from analysis of psychophysical measurements of threshold recovery or from analysis of pigment
regeneration kinetics.
r 2004 Elsevier Ltd. All rights reserved.
Contents
1. Introduction . . . . . . . . ........................................ 309
1.1. Introduction to psychophysical dark adaptation . . . . . . . . . . . . . . . . . .......... 309
1.2. Historical overview of dark adaptation, pigment regeneration, and the retinoid cycle . . . . . . . . 311
1.3. Extraction of data from previous studies . . . . . . . . . . . . . . . . . . . . . .......... 313absorption from the photoreceptor outer segment, in recycling the released retinoid to its original isomeric form as 11-cis retinal,
and in regenerating the visual pigment rhodopsin. Then we analyse the time-course of three aspects of human dark adaptation: thefront matter r 2004 Elsevier Ltd. All rights reserved.
teyeres.2004.03.001

ARTICLE IN PRESS
2.4. Primary steps in the retinoid processing cycle . . . . . . . . . . . . . . . . . . .......... 322
2.4.1. Step 1: Photoisomerization . . . . . . . . . ........................ 322
2.4.2. Step 2: Metarhodopsin transitions . . . . . . ........................ 322
2.4.3. Step 3: Metarhodopsin decay: hydrolysis of the Schiff-base bond . . . . . . . . . . . . . . 323
2.4.4. Kinetics of metarhodopsin formation and decay in the human retina . . . . . . . . . . . . 324
2.4.5. Steps 4 and 5: Oxidation of all-trans retinal by RDH and release of retinol . . . . . . . . 325
2.4.6. Step 6: Condensation product and its removal by the ABCR transporter . . . . . . . . . 325
2.4.7. Step 7: Transport of all-trans retinol across the IPM and within the RPE . . . . . . . . . 326
2.4.8. Step 8: Esterification of retinol to retinyl esters by LRAT. . . . . . . . . . . . . . . . . 326
2.4.9. Step 9: Isomerization and hydrolysis of all-trans retinyl ester to 11-cis retinol . . . . . . . 326
2.4.10. Step 10: Oxidation of 11-cis retinol to 11-cis retinal by 11-cis RDH............ 327
2.4.11. Step 11: Delivery of 11-cis retinal to opsin in the outer segments . . . . . . . . . . . . . 327
2.4.12. Step 12: Non-covalent binding of 11-cis retinal to opsin . . . . . . . . . . . . . . . . . . 328
2.4.13. Step 13: Schiff base bond formation and stabilization of rhodopsin . . . . . . . . . . . . 328
2.5. Subsidiary steps related to the retinoid cycle . . . . . . . . . . . . . . . . . . . .......... 329
2.5.1. Step 14: Shut-off of activated rhodopsin by rhodopsin kinase (RK) and arrestin (Arr) . . . 329
2.5.2. Step 15: Light-driven formation of 11-cis retinoid in the RPE by RGR . . . . . . . . . . 329
2.5.3. Possible additional pathway for cone photoreceptors . . . . . . . . . . . . . . . . . . . . 330
3. Normal dark adaptation and pigment regeneration in the living human eye . ............... 330
3.1. Human scotopic dark adaptation: normal psychophysics . . . . . . . . . . . . .......... 330
3.1.1. Component S2 . . . . . . . . . . . . . . . . ........................ 331
3.1.2. Rate-limited behaviour of S2 for larger bleaches . . . . . . . . . . . . . . . . . . . . . . 331
3.1.3. Components of recovery, and features that distinguish S2 . . . . . . . . . . . . . . . . . 332
3.1.4. Component S3 . . . . . . . . . . . . . . . . ........................ 332
3.2. Human rod photoreceptor recovery following bleaches: the ERG a-wave . . . . .......... 333
3.3. Interpretation of the similarity of dark adaptation and a-wave recoveries . . . . .......... 334
3.4. Extraction of human rhodopsin regeneration from psychophysical and a-wave recoveries . . . . . 334
3.5. Comparison with rhodopsin regeneration from reflection densitometry . . . . . .......... 335
3.6. Human cone pigment regeneration . . . . . . . . . . . . . . . . . . . . . . . . .......... 336
3.7. Rod dark adaptation at earlier times: results from rod monochromats . . . . . .......... 336
4. A molecular model of dark adaptation and pigment regeneration . . . . . . ............... 338
4.1. Description of the MLP model of opsin removal . . . . . . . . . . . . . . . . .......... 338
4.2. Mathematics of the MLP model ................................... 339
4.2.1. Differential equation for the rate of recovery ........................ 339
4.2.2. Solution for recovery in darkness after a bleach (ignoring metarhodopsin decay) . . . . . 340
4.3. Predictions of the MLP model . ................................... 341
4.3.1. Pigment regeneration kinetics . . . . . . . . ........................ 341
4.3.2. Parallel recoveries for psychophysical component S2 . . . . . . . . . . . . . . . . . . . . 341
4.3.3. Dependence of slope of log threshold on concentration of 11-cis retinal . . . . . . . . . . 343
4.3.4. Estimation of the magnitude of the semi-saturation constant K
m
.............. 343
4.3.5. Vertical scaling of component S2 . . . . . . ........................ 344
4.3.6. Rate-limited behaviour of component S2 for large bleaches . . . . . . . . . . . . . . . . . 344
4.3.7. Effect of altered delivery parameters: concentration C, and resistance R .......... 344
4.3.8. Concentration, quantity, synthesis, and degradation of 11-cis retinal . . . . . . . . . . . . 344
4.4. Allowance for opsin formation through metarhodopsin decay . . . . . . . . . . .......... 345
4.4.1. Kinetics of metarhodopsin decay . . . . . . ........................ 345
4.4.2. Predicted effect on pigment regeneration . . ........................ 347
4.5. Summary and critique of modelling . . . . . . . . . . . . . . . . . . . . . . . .......... 347
5. Abnormalities of human dark adaptation and pigment regeneration . . . . ............... 348
5.1. Oguchi disease (mutations of RK or Arr) . . . . . . . . . . . . . . . . . . . . .......... 349
5.1.1. Three studies from the literature . . . . . . . ........................ 349
5.1.2. Pigment regeneration in Oguchi disease . . . ........................ 350
5.1.3. Dark adaptation in Oguchi disease . . . . . ........................ 351
5.1.4. Molecular basis of threshold elevation in Oguchi disease . . . . . . . . . . . . . . . . . . 351
5.1.5. Conclusions from Oguchi disease . . . . . . ........................ 352
5.2. Vitamin A deficiency (VAD) . . ................................... 353
5.2.1. Slowed rhodopsin regeneration and dark adaptation in human subjects . . . . . . . . . . 354
5.2.2. Plateaux of rod dark adaptation in VAD . . ........................ 355
5.2.3. Explanation of plateaux: concentration of 11-cis retinal reduced to zero . . . . . . . . . . 355
T.D. Lamb, E.N. Pugh Jr. / Progress in Retinal and Eye Research 23 (2004) 307–380308