- •An Organ of Exquisite Perfection
- •Optical Path
- •Retinal Photoreception
- •Photoreception Optics
- •Photoreception Biochemistry
- •Membrane Voltages
- •Blind Spot
- •Retinal Pathways
- •Through Pathway
- •Receptive Fields
- •Lateral Pathway
- •Retinal Ganglion Cells
- •Retinal Glia
- •References
- •Development of the Foveal Specialization
- •Introduction
- •Foveal Development
- •Specification of Foveal Location
- •Formation of a Rod-Free Zone
- •Cones, Ganglion Cells, and Initial Pit Formation
- •Deep Foveal Pit Formation
- •Foveal Hypoplasia
- •Conclusions and Perspectives
- •Acknowledgments
- •References
- •An Update on the Regulation of Rod Photoreceptor Development
- •Introduction
- •Brief Overview of Retinal Development and Early Stages of Rod Photoreceptor Differentiation
- •Transcription Factors
- •Basic Helix-Loop-Helix Genes
- •Nuclear Receptors
- •Retinoic Acid/Retinoic Acid Receptors
- •Wnt/Frizzled Pathway
- •Taurine
- •Ciliary Neurotrophic Factor/Leukemia Inhibitory Factor/Pleiotrophin/Signal Transducer and Activators of Transcription 3/SOCS
- •Conclusions and Future Prospects
- •References
- •Introduction
- •Retinal Adhesion
- •Physiology of Retinal Adhesion
- •Molecular Mechanisms of Retinal Adhesion
- •Significance of Retinal Adhesion for Retinal Function
- •Photoreceptor Outer Segment Renewal
- •Physiology of Outer Segment Disk Assembly and Disk Shedding
- •Physiology of RPE Engulfment of Shed Outer Segment Fragments
- •Molecular Mechanisms of Shedding and RPE Phagocytosis
- •Significance of Photoreceptor Outer Segment Renewal for Retinal Function
- •Perspective
- •Acknowledgments
- •References
- •Molecular Biology of IRBP and Its Role in the Visual Cycle
- •Introduction
- •IRBP Protein Studies
- •IRBP Null Mice
- •IRBP Induces Experimental Autoimmune Uveitis
- •IRBP Expression During Development
- •Variability in IRBP Expression
- •Molecular Biology of IRBP
- •IRBP Genomic Cloning
- •Evolution of IRBP
- •Identification of DNA cis-Acting Controlling Elements: In Vitro and In Vivo Experiments
- •Transcription Factors and their Role in the Control of IRBP Expression
- •Rx/rax Transcription Factor
- •NrL Transcription Factor
- •Crx Transcription Factor
- •OTX2 Transcription Factor
- •Transgenic Mice
- •Repressors of IRBP Gene Expression
- •Summary and Conjecture
- •Acknowledgments
- •References
- •Regulation of Photoresponses by Phosphorylation
- •Introduction
- •Cone-Specific Kinase, GRK7
- •Protein Kinase C
- •Cyclin-Dependent Kinase
- •Tyrosine Kinases
- •Protein Phosphatases
- •Conclusion
- •References
- •The cGMP Signaling Pathway in Retinal Photoreceptors and the Central Role of Photoreceptor Phosphodiesterase (PDE6)
- •Regulation of Intracellular cGMP Levels in Photoreceptor Cells
- •Downstream Targets of cGMP Action in Photoreceptor Cells
- •cGMP-Dependent Protein Kinase
- •Cyclic Nucleotide-Gated Ion Channels
- •PDE6 Is a High-Affinity cGMP-Binding Protein
- •Compartmentation of cGMP Signaling in Photoreceptor Outer Segments
- •Physiology of the Photoreceptor Response to Light
- •Biochemical Cascade of Visual Excitation
- •Central Components of the cGMP Signaling Pathway
- •Termination and Adaptation of the Light Response
- •Deactivation of Rhodopsin
- •Deactivation of Transducin
- •Deactivation of PDE6
- •Activation of GC
- •Regulation of the CNG Ion Channel
- •Photoreceptor PDE (PDE6) Structure and Function
- •The Cyclic Nucleotide Phosphodiesterase Superfamily
- •Subunit Composition of Rod and Cone PDE6 Holoenzyme
- •Catalytic Subunit
- •Regulatory GAF Domain
- •Catalytic Domain
- •C-Terminal Prenylation
- •PDE6 Has Evolved to Meet the Special Demands of the Central Effector of Visual Transduction
- •PDE6 Regulation
- •Transducin Activation of Rod PDE6 During Visual Excitation
- •Functions of the Regulatory cGMP-Binding GAF Domains of PDE6
- •Potential PDE6 Regulatory Binding Proteins
- •Glutamic Acid-Rich Protein 2
- •Conclusions
- •Acknowledgments
- •References
- •Rhodopsin Structure, Function, and Involvement in Retinitis Pigmentosa
- •Introduction
- •Historical Perspective
- •Rhodopsin, Localization, and Signaling
- •Dark State and Activation
- •Structural Analysis
- •Electron Cryomicroscopy and Crystal Structure
- •Nuclear Magnetic Resonance
- •Cysteine Mutagenesis and Electron Paramagnetic Resonance
- •Other Approaches
- •Retinitis Pigmentosa
- •Transmembrane RP Rhodopsin Mutants
- •Cytoplasmic RP Rhodopsin Mutants
- •Intradiskal RP Rhodopsin Mutants
- •Implications of Receptor Misfolding
- •Nongenetic Contributions to RP
- •Conclusion
- •References
- •Multiple Signaling Pathways Govern Calcium Homeostasis in Photoreceptor Inner Segments
- •Introduction
- •Overview of Ca2+ Regulation in the Inner Segment
- •Voltage-Operated Calcium Channels Play a Central Role in Inner Segment Calcium Regulation
- •Ca2+ Channels in Rods and Cones
- •Photoreceptor Malfunction and Degeneration
- •Therapeutic Strategies
- •Development
- •Acknowledgments
- •References
- •The Transduction Channels of Rod and Cone Photoreceptors
- •The Role of CNG Channels in Photoreceptor Physiology
- •The Activation Phase of the Light Response
- •Recovery After a Light Stimulus and Adaptation to Continuous Illumination
- •CNG Channels in the Synaptic Transmission of Cone Photoreceptors
- •The Molecular Composition of CNG Channels
- •The Basic Activation Properties of CNG Channels
- •Transmembrane Topology and Functional Domains
- •The Cyclic-Nucleotide-Binding Domain
- •The Amino Terminal Domain and Modulation by Calmodulin
- •The P Region
- •The GARP Domain of CNGB1
- •Modulation by Phosphorylation and All-trans Retinal
- •Synthesis, Maturation, and Targeting of CNG Channels
- •Visual Dysfunction Caused by Mutant CNG Channel Genes
- •References
- •Appendix
- •Visual Dysfunction Caused by Mutant CNG Channel Genes
- •Mutations in CNGA1 and CNGB1 Associated with Retinitis Pigmentosa
- •Mutations in CNGA3 and CNGB3 Associated with Cone Dysfunction
- •References
- •Rhodopsins in Drosophila Color Vision
- •Introduction
- •Anatomy and Molecular Aspects of Color-Sensitive Opsins in the Drosophila Eye
- •Structure of the Drosophila Eye: Ommatidia, Photoreceptors, and Rhodopsins
- •Molecular Genetics and Evolution of Rh5 and Rh6
- •Development and Patterning of Rhodopsins for Drosophila Color Vision
- •Mutually Exclusive Rhodopsin Expression
- •Transcription Factors Specify Outer from Inner Photoreceptors and Distinguish R7 from R8
- •A Stochastic Decision Induces Rhodopsins in R7 Photoreceptor
- •A Bistable Feedback Loop Specifies R8 Photoreceptor Subtype and Expression of Rh5 and Rh6
- •Comparison Between Mammalian and Drosophila Color Vision Rhodopsins
- •Human Color-Sensitive Opsins
- •Conclusion
- •References
- •INAD Signaling Complex of Drosophila Photoreceptors
- •Introduction
- •Identification of the INAD Signaling Complex
- •Function of the INAD Signaling Complex
- •Information Transfer From Rhodopsin to the Signaling Complex BY the Visual G Protein
- •Signaling Complexes in Vertebrate Photoreceptor Cells
- •Acknowledgments
- •References
- •Visual Signal Processing in the Inner Retina
- •Introduction
- •Visual Information is First Processed in the OPL
- •Bipolar Cells form Parallel Pathways and Provide Excitatory Input to the IPL
- •Functional Stratification of the IPL
- •ON and OFF Response Stratification
- •Sustained and Transient Response Stratification
- •Synaptic Mechanisms Shape Excitatory Signals in the IPL
- •Glutamate Release Is Tonic and Graded
- •Transporters Terminate Excitatory Signaling to Ganglion Cells
- •Postsynaptic Glutamate Receptor Properties Shape Ganglion Cell Excitation
- •Modulating Glutamate Release Shapes Excitatory Responses
- •Amacrine Cells Mediate Inhibition in the IPL
- •Presynaptic Inhibition
- •Asymmetric Presynaptic Inhibition
- •Presynaptic Inhibition Is Filtered by GABA Receptor Properties
- •Presynaptic Inhibition May Be Shaped by Transmitter Release Differences
- •Glycine, the Other Inhibitory Transmitter
- •Parallel Ganglion Cell Output Pathways
- •Ganglion Cells Encode Color Information
- •Directional-Selective Ganglion Cells
- •Intrinsically Photosensitive Ganglion Cells
- •Conclusions
- •References
- •Human Cone Spectral Sensitivities and Color Vision Deficiencies
- •Introduction
- •Overview
- •Transduction
- •Univariance, Monochromacy, Dichromacy, and Trichromacy
- •Trichromacy and Color-Matching Functions
- •Cone Spectral Sensitivities
- •Introduction
- •Cone Spectral Sensitivity Measurements
- •From Cone Spectral Sensitivities to Color-Matching Functions
- •Other Factors That Influence Spectral Sensitivity
- •Lens Pigment
- •Macular Pigment
- •Photopigment Optical Density
- •Changes with Eccentricity
- •Congenital Color Vision Deficiencies
- •Protan and Deutan Defects
- •Protanopia and Deuteranopia
- •Photopigment Variability and Protanomaly and Deuteranomaly
- •Tritanopia
- •Monochromacies
- •Cone Monochromacies
- •Rod Monochromacy
- •Conclusions
- •Acknowledgment
- •References
- •Luminous Efficiency Functions
- •Introduction
- •The Need for Luminous Efficiency
- •Psychophysical Measures of Luminous Efficiency
- •Factors that Influence Luminous Efficiency
- •Scotopic (Rod) Luminous Efficiency Function
- •Introduction
- •Univariance
- •International Standard
- •Photopic (Cone) Luminous Efficiency Function
- •Introduction
- •International Standards
- •Other Photopic (Nonadditive) Luminous Efficiency Functions
- •Mesopic (Rod-Cone) Luminous Efficiency Functions
- •Introduction
- •Models of Mesopic Luminous Efficiency
- •International Standard
- •Individual Differences Influencing Luminous Efficiency
- •Attenuation of Spectral Light by the Lens and Other Ocular Media
- •Attenuation of Spectral Light by the Macular Pigment
- •Optical Densities of the Photopigments
- •Relative Numbers of L and M Cones
- •Cone Pigment Polymorphisms
- •Directional Sensitivity
- •Variations in the Contribution of Chromatic Channels
- •Conclusions
- •References
- •Cone Pigments and Vision in the Mouse
- •Introduction
- •Prevalence and Spatial Distribution of Mouse Cones
- •Mouse Strain Variations
- •Mouse Cone Pigments
- •Cone Pigment Spectra
- •Evolution and Spectral Tuning of Mouse Cone Pigments
- •Regional Distribution of Mouse Cone Pigments
- •Expression of Mouse Cone Pigments
- •Cone Signal Pathways in the Mouse Retina
- •Cone-Based Vision in Mice
- •Assessment Techniques
- •Spectral Sensitivity
- •Spatial and Temporal Sensitivity
- •Color Vision
- •Targeted Deletions of Rods or Cones
- •Addition of New Cone Pigments
- •Mouse and Human Cone Vision
- •Acknowledgment
- •References
- •Multifocal Oscillatory Potentials of the Human Retina
- •Introduction
- •Recording Techniques
- •Underlying Mechanisms
- •The Influence of age and Gender
- •Disease-Related Changes
- •Origins of Single Potentials
- •Dichromats
- •Congenital Stationary Night Blindness
- •Topographical Alterations
- •Diabetes
- •Retinal Vessel Occlusion
- •Glaucoma
- •General Alterations
- •Vigabatrin Treatment
- •Conclusion
- •References
- •The Aging of the Retina
- •Introduction
- •Morphological Alterations
- •Neural Changes
- •Retinal Pigment Epithelium and Lipofuscin Formation
- •Bruch’s Membrane and Choroid
- •Retinal Function Changes
- •Age-Related Macular Disease
- •Conclusions
- •References
- •Aging of the Retinal Pigment Epithelium
- •Introduction
- •Aging Changes In the Fundus
- •Age-Related Changes In RPE Morphology
- •Melanosomes
- •Lipofuscin
- •Pigment Complexes
- •Mitochondria
- •Bruch’s Membrane
- •Functional Consequences of RPE Cell Aging
- •Phagocytic Load
- •The Effect of Lipofuscin on the RPE
- •Melanosomes
- •Antioxidant Capacity of the RPE
- •Lysosomal Enzyme Activity
- •Mitochondrial Damage in the RPE
- •Bruch’s Membrane Aging
- •Oxidative Stress and RPE Aging
- •The Relationship Between Aging and Retinal Pathologies
- •Summary and Conclusions
- •References
- •Visual Transduction and Age-Related Changes in Lipofuscin
- •Introduction: What is Lipofuscin?
- •Lipofuscin of the Retinal Pigment Epithelium
- •Composition of RPE Lipofuscin
- •Fluorescence Properties of RPE Lipofuscin
- •A2E as a Marker of Lipofuscin Accumulation
- •Factors Affecting Accumulation of RPE Lipofuscin
- •Phagocytosis and Autophagy
- •Role of Lysosomal Degradation
- •Role of Oxidative Stress
- •Role of Phototransduction in Accumulation of RPE Lipofuscin
- •Transient Buildup of All-trans Retinal in Photoreceptor Outer Segments as a Critical Factor for Lipofuscin Formation
- •Inhibition of the Retinoid Cycle Inhibits Lipofuscin Accumulation
- •Role of Exposure of the Retina to Light
- •Other Factors Contributing to Accelerated Accumulation of RPE Lipofuscin
- •A Hypothetical Scenario of Biogenesis of RPE Lipofuscin
- •Effects of Lipofuscin on RPE Function and Viability
- •Photoreactivity of RPE Lipofuscin
- •Toxicity of RPE Lipofuscin
- •Effects of Lipofuscin Components and Oxidative Stress in the RPE on Proinflammatory and Angiogenic Signaling
- •Approaches to Diminish Lipofuscin Accumulation or Lipofuscin-Induced Damage
- •Conclusions
- •References
- •A Nonspecific System Provides Nonphotic Information for the Biological Clock
- •Introduction
- •Nonphotic Information
- •Nonspecific Systems
- •Ascending Reticular-Activating System
- •Orexin/Hypocretin Projection
- •Intergeniculate Leaflet of the Thalamus
- •Anatomy
- •The Pharmacology of the IGL
- •Chronobiology
- •The Electrophysiology of the IGL
- •IGL as an Integrator of Photic and Nonphotic Information
- •Conclusions
- •References
- •The Circadian Clock: Physiology, Genes, and Disease
- •Introduction
- •Circadian Rhythms in Physiology and Behavior
- •Circadian Rhythms in Visual Function
- •Entrainment
- •Anatomy
- •The Suprachiasmatic Nucleus
- •Inputs to the SCN
- •Peripheral Oscillators
- •A Clock in the Eye
- •Oscillators Outside the Nervous System
- •Clock Genes
- •Human Implications
- •Summary
- •References
Luminous Efficiency Functions |
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1924 CIE V (λ) |
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1964 CIE V10(λ) |
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Fig. 3. Photopic luminous efficiency functions for 2° and 10° central viewing conditions. The CIE (Commission Internationale de l’ Éclairage, International Lighting Commission) 1924
2° V(λ) function (open circle) is compared with the newly derived 2° V*(λ) function (solid black |
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line; [44]). The CIE 1964 10° V10(λ) [gray line; also known as the y10(l) color-matching function) |
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is compared with the new V |
*(λ) function. |
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International Standards
Additive Functions for 2° Viewing Fields
In 1924, the CIE [42] established a luminous efficiency function V(λ) for 2° photopic (cone) vision (see Fig. 3; the values can be downloaded from the Web site http://www.cvrl.org), which has since become the standard (mean) photopic observer for business and industry [42, 43]. In visual science, V(λ) or its variants have been assumed to correspond to the spectral sensitivity of a hypothetical human postreceptoral “luminance” channel with additive inputs from the L and M cones (e.g., [8]). Nevertheless, such wide acceptance overlooks serious flaws and complications in V(λ)’s derivation. First, the derivation of V(λ) was not based exclusively on psychophysical techniques that obey additivity. Rather, it is a speculative hybrid function, artificially smoothed and assembled from divergent data measured using both “additive” and “nonadditive” techniques at several laboratories (see [11, 12, 43, 44]). Its most conspicuous flaw is that it seriously underestimates luminous efficiency at short wavelengths (see, for discussion, [22]). Although two attempts were later made to correct this problem [45, 46], the modifications generated functions that are far removed from actual data.
The CIE did not adequately specify V(λ) for adaptation level. In fact, the specific adaptive or desensitization states of the L and M cones were not held constant in the various
336 Sharpe and Stockman
experiments (see, for a comment, [44]). The CIE was also unable to take into account variations in genotype, in particular the L-cone polymorphic variation that primarily affects long-wavelength sensitivity (see Chapter 14 on human cone spectral sensitivities and color vision deficiencies).
To correct these problems, Sharpe et al. [44] determined a new luminous efficiency function for 2° photopic viewing conditions, V*(λ) (see Fig. 3; the values can be downloaded from the Web site http://www.cvrl.org or from the online article), based exclusively on HFP measurements, which obey additivity, in 40 genotyped observers whose L-cone polymorphic variant was determined. The V*(λ) and the CIE 1924 V(λ) functions can be directly compared in Fig. 3. The two functions differ most conspicuously at short wavelengths below 500 nm.
The new function was obtained under neutral adaptation that corresponds to a specific and reproducible phase of natural daylight (CIE standard illuminant D65) adaptation. Moreover, it is defined as a linear combination of the Stockman and Sharpe [23] L- and
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V*(l)=[al(l)+ m(l)]/c, |
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where a is the relative L-cone weight, and c is a constant that scales the function so
¯ l − l
that it peaks at unity. In relative quantal units, with l( ) and m ( ) themselves both normalized to unity quantal peak, a = 1.890000 and c = 2.80361; in relative energy units,
¯ l − l
with l( ) and m( ) both normalized to unity energy peak, a = 1.98065 and c = 2.87091 [44]. The S-cone contribution is so small, and anyhow is so complexly dependent on temporal frequency and adaptation, that it can be safely ignored in defining photopic luminous efficiency under conditions that obey additivity (for a full discussion of this point, see [44, 47]).
Note that these constants define photopic luminous efficiency when the eye is adapted to a specific state of “daylight” (D65) adaptation. Necessarily, different states of adaptation will lead to different constants and different luminous efficiency functions, so that the applicability of V*(λ) is unavoidably limited. However, once photopic luminous efficiency is defined in terms of the L- and M-cone sensitivities, it becomes possible to define it for other states of chromatic adaptation merely by investigating and modeling the changes that occur in the relative contributions of the L and M cones as a function of the effective wavelength of the adapting field.
Accordingly, Stockman, Jägle, Jagla, and Sharpe [47] have investigated the dependence of V*(λ) on adapting field chromaticity. As expected, through selective cone adaptation or desensitization, short-wavelength fields increase a by decreasing the relative contribution of the M cones, and long-wavelength fields decrease a by decreasing the relative contribution of the L cones (see Fig. 4).
A generalized formula is suggested in [47].
Additive Functions for 10° Viewing Fields
Until recently, the photopic luminous efficiency function that was considered most representative for large centrally viewed fields was the 1964 CIE V10 (λ) function for 10° fields, which was derived from large-field color-matching data and luminous
Luminous Efficiency Functions |
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430: 2.39 |
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462: 3.41 |
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495: 2.79 |
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535: 1.83 |
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577: 0.79 |
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589: 0.57 |
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670: 0.30 |
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Fig. 4. The 25-Hz heterochromatic flicker photometric (HFP) luminous efficiency functions for the same subject measured on spectral backgrounds ranging from 430 to 670 nm. The curve drawn through each set of data is the best-fitting version of Eq. 1. The background wavelength (in nanometers) and the derived L-cone weighting factor a (from Eq. 1) are noted to the right of each curve. (From [47].) Generally, the L-cone weight or relative contribution of the L cones increases for short-wavelength adaptation and decreases for long-wavelength adaptation. However, the change is not linear with adapting wavelength and is complicated by changes in chromatic adaptation caused by the targets (see [47]).
efficiency measurements made in a subset of subjects at four wavelengths [12].
− l
It is by design identical to the y10( ) color-matching function of the CIE 1964 supplementary standard colorimetric observer. This function is shown in Fig. 3 together with the 2° V(λ) and V*(λ) functions (the values can be downloaded from the Web site http://www.cvrl.org). However, a technical committee of the CIE has recommended that a new photopic luminosity function V10*(λ), derived from the V*(λ) function by making corrections for the differences in the mean optical density of the
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Fig. 5. Spectral filtering by the optic media. The standard or average optical density of the lens and other ocular media as a function of wavelength is shown (solid black line; [23]). Also shown is the standard or average optical density of the macular pigment as a function of wavelength for small (2°; solid gray line) and large (10°; dashed gray line) centrally viewed fields. (After [23].)
macular pigment for 2° and 10° viewing fields (see the section on attenuation of spectral light by the macular pigment and Fig. 5), should replace the 1964 CIE V10(λ) function in physiologically relevant colorimetric and photometric systems. The new V10*(λ) function is shown in Fig. 3, in which it can be compared directly with the 1964 CIE V10 (λ) function. There are only slight discrepancies, mostly at short wavelengths.
Other Photopic (Nonadditive) Luminous Efficiency Functions
The 1924 CIE V(λ) function and the V*(λ) function are not representative of luminous efficiency functions based on HBM. These tend to be broader and to exhibit more than one peak. The CIE Technical Committee 1.4 Vision (TC 1.4) recommended a 2° brightness-matching luminous efficiency function based on a number of studies to supplement V(λ) [12]. Revised brightness-matching standard luminous efficiency functions for 2° and 10° viewing fields [48] and for point sources [49] have since been derived. The 10° field function differs from the 2° function only at short wavelengths, from 410 through 520 nm, when the functions are normalized at 570 nm. The difference is attributed to absorption by the macular pigment. The point source function can be approximated by Judd’s [45] modification of the CIE 1924 V(λ) function. It is pertinent to point out that these functions, based on HBM, will not obey Abney’s law, so their application is very limited.
