Studies of functional variability in the compound eyes of flies reveal superior temporal resolution of photoreceptors from the frontal areas that mediate binocular vision, and in males mate recognition and pursuit. However, the mechanisms underlying differences in performance are not known. Here, we investigated properties of hover fly Volucella pellucens photoreceptors from two regions of the retina, the frontal-dorsal “love spot” and the lateral one. Morphologically, the microvilli of the frontal-dorsal photoreceptors were relatively few in number per rhabdomere cross-section, short and narrow. In electrophysiological experiments involving stimulation with prolonged white-noise and natural time intensity series, frontal-dorsal photoreceptors demonstrated comparatively high corner frequencies and information rates. Investigation of possible mechanisms responsible for their superior performance revealed significant differences in the properties of quantum bumps, and, unexpectedly, relatively high absolute sensitivity of the frontal-dorsal photoreceptors. Analysis of light adaptation indicated that photoreceptors from two regions adapt similarly but because frontal-dorsal photoreceptors were depolarized much stronger by the same stimuli than the lateral photoreceptors, they reached a deeper state of adaptation associated with higher corner frequencies of light response. Recordings from the photoreceptor axons were characterized by spike-like events that can significantly expand the frequency response range. Seamless integration of spikes into the graded voltage responses was enabled by light adaptation mechanisms that accelerate kinetics and decrease duration of depolarizing light response transients.

Vision loss, among the most feared complications of diabetes, is primarily caused by diabetic retinopathy, a disease that manifests in well-recognized, characteristic microvascular lesions. The reasons for retinal susceptibility to damage in diabetes are unclear, especially considering that microvascular networks are found in all tissues. However, the unique metabolic demands of retinal neurons could account for their vulnerability in diabetes. Photoreceptors are the first neurons in the visual circuit and are also the most energy-demanding cells of the retina. Here, we review experimental and clinical evidence linking photoreceptors to the development of diabetic retinopathy. We then describe the influence of retinal illumination on photoreceptor metabolism, effects of light modulation on the severity of diabetic retinopathy, and recent clinical trials testing the treatment of diabetic retinopathy with interventions that impact photoreceptor metabolism. Finally, we introduce several possible mechanisms that could link photoreceptor responses to light and the development of retinal vascular disease in diabetes. Collectively, these concepts form the basis for a growing body of investigative efforts aimed at developing novel pharmacologic and nonpharmacologic tools that target photoreceptor physiology to treat a very common cause of blindness across the world.

Variability in the electrophysiological properties of homotypic photoreceptors is widespread and is thought to facilitate functioning under disparate illumination conditions. Compound eyes of insects have three sources of variability: inter-individual, intra-individual, and intra-ommatidial, the latter two overlapping. Here, I explored the causes of variability in Periplaneta americana, a nocturnal insect characterized by highly variable photoreceptor responses. By recording from photoreceptors in dissociated ommatidia, including consecutive recordings from photoreceptors in the same ommatidium (SO), I studied the variability of six properties: whole-cell membrane capacitance (Cm), phototransduction latency, maximal conductance (Gmax) and the slope factor of the sustained Kv current, absolute sensitivity in dim light, and sustained light-induced current (LIC) amplitude in bright light. Coefficient of variation (CV) metrics were used to compare variances in four experimental groups: SO, same animal (SA), all data combined “full sample” (FS), and full sample of all SO recordings (FSSO). For the normally distributed parameters Cm, Gmax, slope factor, and latency, the highest CV values were found in FS and FSSO, intermediate in SA, and the lowest in SO. On average, SO variance accounted for 47% of the full-sample variance in these four parameters. Absolute sensitivity and LIC values were not normally distributed, and the differences in variability between SO and FS/FSSO groups were smaller than for the other four parameters. These results indicate two main sources of variability, intra-ommatidial and inter-individual. Inter-individual variability was investigated by exposing adult cockroaches to constant light or dark for several months. In both groups, the majority of CV measures for the six parameters decreased compared to control, indicating substantial contribution of phenotypic plasticity to inter-individual differences. Analysis of variability of resting potential and elementary voltage responses revealed that resting potential is mainly determined by the sustained Kv conductance, whereas voltage bump amplitude is mainly determined by current bump amplitude and Cm.

Vision loss caused by the death of photoreceptors is the leading cause of irreversible blindness in the developed world. Rapid advances in stem cell biology and techniques in cell transplantation have made photoreceptor replacement by transplantation a very plausible therapeutic strategy. These advances include the demonstration of restoration of vision following photoreceptor transplantation and the generation of transplantable populations of donor cells from stem cells. In this review, we present a brief overview of the recent progress in photoreceptor transplantation. We then consider in more detail some of the challenges presented by the degenerating retinal environment that must play host to these transplanted cells, how these may influence transplanted photoreceptor cell integration and survival, and some of the progress in developing strategies to circumnavigate these issues.

Electrical coupling of photoreceptors through gap junctions suppresses voltage noise, routes rod signals into cone pathways, expands the dynamic range of rod photoreceptors in high scotopic and mesopic illumination, and improves detection of contrast and small stimuli. In essentially all vertebrates, connexin 35/36 (gene homologs Cx36 in mammals, Cx35 in other vertebrates) is the major gap junction protein observed in photoreceptors, mediating rod–cone, cone–cone, and possibly rod–rod communication. Photoreceptor coupling is dynamically controlled by the day/night cycle and light/dark adaptation, and is directly correlated with phosphorylation of Cx35/36 at two sites, serine110 and serine 276/293 (homologous sites in teleost fish and mammals, respectively). Activity of protein kinase A (PKA) plays a key role during this process. Previous studies have shown that activation of dopamine D4 receptors on photoreceptors inhibits adenylyl cyclase, down-regulates cAMP and PKA activity, and leads to photoreceptor uncoupling, imposing the daytime/light condition. In this study, we explored the role of adenosine, a nighttime signal with a high extracellular concentration at night and a low concentration in the day, in regulating photoreceptor coupling by examining photoreceptor Cx35 phosphorylation in zebrafish retina. Adenosine enhanced photoreceptor Cx35 phosphorylation in daytime, but with a complex dose–response curve. Selective pharmacological manipulations revealed that adenosine A2a receptors provide a potent positive drive to phosphorylate photoreceptor Cx35 under the influence of endogenous adenosine at night. A2a receptors can be activated in the daytime as well by micromolar exogenous adenosine. However, the higher affinity adenosine A1 receptors are also present and have an antagonistic though less potent effect. Thus, the nighttime/darkness signal adenosine provides a net positive drive on Cx35 phosphorylation at night, working in opposition to dopamine to regulate photoreceptor coupling via a push–pull mechanism. However, the lower concentration of adenosine present in the daytime actually reinforces the dopamine signal through action on the A1 receptor.

Photostasis is a phenomenon where the photoreceptor outer segment (OS) length and its rhodopsin content vary depending on environmental lighting. When light is reduced for extended periods, it is argued that OS lengthen and its rhodopsin concentration rises to increase photon capture in darker environment. Increases in OS length may occur because the retinal pigment epithelium (RPE) cells reduce OS consumption in prolonged darkness. But sample sizes in assessing changes in OS length have been small, and results highly varied with no statistical analysis ever offered. Further, animals used were often albinos, which have abnormal RPE cells. Here we keep pigmented and albino mice for 21 days in darkness and compare OS length with those in a normal 12:12 light/dark environment. We measured approximately 1300 OS but found no statistically significant difference in their lengths between light and dark groups in either pigmentation phenotype, although there was a small trend in the data favoring OS extension in the dark. Given that earlier studies were undertaken on limited samples with no statistical analysis, our data pose serious questions for the notion of mammalian photostasis in terms of significant OS plasticity.

Dynamin proteins are involved in vesicle generation, providing mechanical force to excise newly formed vesicles from membranes of cellular compartments. In the brain, dynamin-1, dynamin-2, and dynamin-3 have been well studied; however, their function in the retina remains elusive. A retina-specific splice variant of dynamin-1 interacts with the photoreceptor-specific protein Tubby-like protein 1 (Tulp1), which when mutated causes an early onset form of autosomal recessive retinitis pigmentosa. Here, we investigated the role of the dynamins in the retina, using immunohistochemistry to localize dynamin-1, dynamin-2, and dynamin-3 and immunoprecipitation followed by mass spectrometry to explore dynamin-1 interacting proteins in mouse retina. Dynamin-2 is primarily confined to the inner segment compartment of photoreceptors, suggesting a role in outer segment protein transport. Dynamin-3 is present in the terminals of photoreceptors and dendrites of second-order neurons but is most pronounced in the inner plexiform layer where second-order neurons relay signals from photoreceptors. Dynamin-1 appears to be the dominant isoform in the retina and is present throughout the retina and in multiple compartments of the photoreceptor cell. This suggests that it may function in multiple cellular pathways. Surprisingly, dynamin-1 expression and localization did not appear to be disrupted in tulp1−/− mice. Immunoprecipitation experiments reveal that dynamin-1 associates primarily with proteins involved in cytoskeletal-based membrane dynamics. This finding is confirmed by western blot analysis. Results further implicate dynamin-1 in vesicular protein transport processes relevant to synaptic and post-Golgi pathways and indicate a possible role in photoreceptor stability.

Eye evolution is driven by the evolution of visually guided behavior. Accumulation of gradually more demanding behaviors have continuously increased the performance requirements on the photoreceptor organs. Starting with nondirectional photoreception, I argue for an evolutionary sequence continuing with directional photoreception, low-resolution vision, and finally, high-resolution vision. Calculations of the physical requirements for these four sensory tasks show that they correlate with major innovations in eye evolution and thus work as a relevant classification for a functional analysis of eye evolution. Together with existing molecular and morphological data, the functional analysis suggests that urbilateria had a simple set of rhabdomeric and ciliary receptors used for directional photoreception, and that organ duplications, positional shifts and functional shifts account for the diverse patterns of eyes and photoreceptors seen in extant animals. The analysis also suggests that directional photoreception evolved independently at least twice before the last common ancestor of bilateria and proceeded several times independently to true vision in different bilaterian and cnidarian groups. This scenario is compatible with Pax-gene expression in eye development in the different animal groups. The whole process from the first opsin to high-resolution vision took about 170 million years and was largely completed by the onset of the Cambrian, about 530 million years ago. Evolution from shadow detectors to multiple directional photoreceptors has further led to secondary cases of eye evolution in bivalves, fan worms, and chitons.

Seeds have long been a model system for studying the intricacies of phytochrome-mediated light perception and signalling. However, very little is known about how they perceive blue and green light. Cryptochromes and phototropins, the major blue-light receptors in plants, are increasingly well-studied in vegetative tissues, but their role in light perception in seeds largely remains a mystery. Green light elicits a number of responses in plants that cannot be explained by the action of any of the known photoreceptors, and some seeds are apparently also capable of perceiving green light. Here, the responses of seeds to blue and green light are collated from a thorough examination of the literature and considered from the perspective of the potential photoreceptor(s) mediating them. Knowledge of how seeds perceive wavelengths that are suboptimal for phytochrome activation could help to improve germination and seedling establishment for both crop and native species.

As described in the companion paper, the synaptic terminal of a cone photoreceptor in macaque monkey makes an average of 35 or 46 basal contacts with the tips of the dendrites of its OFF midget bipolar cell. Each basal contact has one or more symmetrically thickened dense regions. These “Outer Densities,” averaging 48 or 67 in number, harbor clusters of ionotropic glutamate receptors and are ~0.8 μm (and ~1-ms diffusion time) from active zones associated with synaptic ribbons. Here, we show similarly appearing “Inner Densities,” averaging 53 or 74 in number, located more proximally on the dendrites of these OFF midget bipolar cells, ~0.4 μm inward from the tips of the dendrites and out of contact with the basal surface of the cone terminal. Compared to desmosome-like junctions, Inner Densities are closer to the terminal and are less dense and less thick. Each Inner Density is shared with another cell, the partners including diffuse bipolar cells, ON midget bipolar cells, and horizontal cells. Given the diversity of the partners, the OFF midget bipolar cells are unlikely to be in a synaptic relationship with the partners. Instead, Inner Densities are near enough to the active zones associated with synaptic ribbons to receive pulses of glutamate at concentrations effective for glutamate receptors. The role of Inner Densities is not known, but they might represent additional clusters of glutamate receptors.

L and M cones, divided into two groups by absorption spectra, have not been distinguished by structure. Here, we report what may be such a difference. We reconstructed the synaptic terminals of 16 non-S cones and the dendritic arbors of their ON and OFF midget bipolar cells from high-magnification electron micrographs of serial thin sections of a small region of macaque fovea. Each cone terminal contacted a similar number (~16) of invaginating central elements provided by its ON midget bipolar cell. By contrast, the numbers of connections between a cone terminal and its OFF midget bipolar cell were grouped into two clusters: 30–37 versus 43–50 basal contacts in the triad-associated position and 41–47 versus 61–74 Outer Densities within those basal contacts. The coefficients of variation of these distributions were all in the range of 10% or lower, characteristic of single populations. If these two clusters correspond to M- and L-cone circuits, the results reveal structural differences between M and L cones and between their corresponding OFF midget bipolar cells.

In the retina, rod bipolar (RBP) cells synapse with many rods, and suppression of rod outer segment and synaptic noise is necessary for their detection of rod single-photon responses (SPRs). Depending on the rods’ signal-to-noise ratio (SNR), the suppression mechanism will likely eliminate some SPRs as well, resulting in decreased quantum efficiency. We examined this synapse in rabbit, where 100 rods converge onto each RBP. Suction electrode recordings showed that rabbit rod SPRs were difficult to distinguish from noise (independent SNR estimates were 2.3 and 2.8). Nonlinear transmission from rods to RBPs improved response detection (SNR = 8.7), but a large portion of the rod SPRs was discarded. For the dimmest flashes, the loss approached 90%. Despite the high rejection ratio, noise of two distinct types was apparent in the RBP traces: low-amplitude rumblings and discrete events that resembled the SPR. The SPR-like event frequency suggests that they result from thermal isomerizations of rhodopsin, which occurred at the rate 0.033/s/rod. The presence of low-amplitude noise is explained by a sigmoidal input–output relationship at the rod—RBP synapse and the input of noisy rods. The rabbit rod SNR and RBP quantum efficiency are the lowest yet reported, suggesting that the quantum efficiency of the rod—RBP synapse may depend on the SNR in rods. These results point to the possibility that fewer photoisomerizations are discarded for species such as primate, which has a higher rod SNR.

With a body length of only 0.3–0.4 mm, the parasitoid wasp Trichogramma evanescens (Westwood) is one of the smallest insects known. Yet, despite its diminutive size, it possesses compound eyes that are of oval shapes, measuring across their long axes in dorsoventral direction 63.39 and 71.11 μm in males and females, respectively. The corresponding facet diameters are 5.90 μm for males and 6.39 μm for females. Owing to the small radii of curvature of the eyes in males (34.59 μm) and females (42.82 μm), individual ommatidia are short with respective lengths of 24.29 and 34.97 μm. The eyes are of the apposition kind, and each ommatidium possesses four cone cells of the eucone type and a centrally fused rhabdom, which throughout its length is formed by no more than eight retinula cells. A ninth cell occupies the place of the eighth retinula cell in the distal third of the rhabdom. The cone is shielded by two primary and six secondary pigment cells, all with no apparent extensions to the basement membrane, unlike the case in larger hymenopterans. The regular and dense packing of the rhabdoms reflects an effective use of space. Calculations on the optics of the eyes of Trichogramma suggest that the eyes need not be diffraction limited, provided they use mostly shorter wavelengths, that is, UV light. Publications on the visual behavior of these wasps confirm Trichogramma’s sensitivity to UV radiation. On the basis of our findings, some general functional conclusions for very small compound eyes are formulated.

To understand how the photoreceptor protein rhodopsin performs in its role as a receptor, its structure needs to be determined at the atomic level. Upon receiving a photon of light, rhodopsin undergoes a change in conformation that allows it to bind and activate the C-protein, transducin. An important future goal should be to determine the structure of both the inactive and the photoactivated state of rhodopsin, R*. This should provide the groundwork necessary for experiments on how rhodopsin achieves its signaling state R*, and how R* functions to activate transducin. To do this, the crystal structure of both rhodopsin and R* must be determined. Few membrane proteins have been successfully crystallized, so this is not a trivial undertaking. Two- or three dimensional crystals of rhodopsin must be prepared that are well ordered, to produce a high-resolution structure. Rhodopsin must be purified to homogeneity and the appropriate detergent(s) selected for crystallization experiments. Long-term thermal stability of the rhodopsin-detergent complex must be achieved in the presence of a precipitant. Two-dimensional crystals may offer advantages in investigating the structure of R*, but the structure obtained may be limited in resolution. It is necessary to work with rhodopsin in the dark, unless suitable light-stable retinal derivatives are developed. Protein engineering of rhodopsin offers attractive opportunities to improve its ability to crystallize, but is presently hindered by the absence of a high-yielding expression system. Knowledge of the structure of rhodopsin will have general importance. Because rhodopsin is a member of the family of C-protein-coupled receptors, knowledge of the structure and the mechanism of action of rhodopsin suggests by analogy how other members of the receptor family may function.

This article evaluates each of the reactions known to be involved in visual transduction as a potential site for the regulation of light adaptation. Extensive evidence suggests that calcium acts as a feedback messenger at several different points and recent work suggests a role for cGMP in regulating the primary excitatory pathway. A conclusion is that adaptation is likely to be regulated by multiple and redundant mechanisms. The goal of future experimentation will be to determine the relative importance of each of these.

Using suction electrodes, photocurrent responses to 100-ms saturating flashes were recorded from isolated retinal rods of the larval-stage tiger salamander (Ambystoma tigrinum). The delay period (Te) that preceded recovery of the dark current by a criterion amount (3 pA) was analyzed in relation to the flash intensity (If), and to the corresponding fractional bleach (R*0/Rtot) of the visual pigment; R*0/Rtot was compared with R*s/Rtot the fractional bleach at which the peak level of activated transducin approaches saturation. Over an approximately 8 In unit range of If that included the predicted value of R*s/Rtot, Te increased linearly with In If. Within the linear range, the slope of the function yielded an apparent exponential time constant (TC) of 1.7 ± 0.2 s (mean ± S.D.). Background light reduced the value of Tc measured at a given flash intensity but preserved a range over which Tc increased linearly with In If; the linear-range slope was similar to that measured in the absence of background light. The intensity dependence of Tc resembles that of a delay (Td) seen in light-scattering experiments on bovine retinas, which describes the period of essentially complete activation of transducin following a bright flash; the slope of the function relating Td and In flash intensity is thought to reflect the lifetime of photoactivated visual pigment (R*) (Pepperberg et al., 1988; Kahlert et al., 1990). The present data suggest that the electrophysiological delay has a similar basis in the deactivation kinetics of R*, and that Tc represents TR* the lifetime of R* in the phototransduction process. The results furthermore suggest a preservation of the “dark-adapted” value of TR* within the investigated range of background intensity.

The effect of light adaptation on the period of photocurrent saturation induced by a bright stimulating flash was examined in rod photoreceptors of the larval-stage tiger salamander (Ambystoma tigrinum). Using suction electrodes, photocurrent responses to brief flashes were recorded from single, isolated rods in the presence and absence of steady background illumination. Background light decreased the saturation period (T) measured at fixed flash intensity (fixed If) and in this respect light-adapted the saturating response. Effects of the background on responses to weak (i.e. subsaturating) and bright flashes were compared with changes in a parameter, where ΔT is the decrease in saturation period, and where TR* is the slope of the line that relates T and ln If in a given state of adaptation. Dark- and light-adapted responses to flash intensities and , respectively, exhibited similar absolute peak photocurrent and falling-phase kinetics when and satisfied the relation, , where Ib is the background intensity. It is argued that ψ approximates the relative PDE*/R* gain of transduction, i.e. the relative peak level of activated cGMP phosphodiesterase (PDE*) produced by a given, small amount of photoactivated visual pigment (R*). Interpreted on this view, the results imply that light adaptation derives largely from a decrease in PDE*/R* gain, rather than from the stimulation of guanylate cyclase activity. The data are consistent with the possibility that modulation of the lifetime of PDE* underlies the background dependence of ψ.

The activities of both protein phosphatases and protein kinases are responsible for the transient changes in the levels of phosphorylation and probably the functions of protein intermediates involved in the biochemical and physiological mechanisms underlying the photoresponse in photoreceptor cells from both vertebrate and invertebrate organisms. Of the known protein serine/threonine phosphatases, various forms of type I (PP 1) and type 2A (PP 2A) protein phosphatases are responsible for dephosphorylating many of the known phosphoproteins including those involved in photoreceptor cell function. In this report, we provide biochemical evidence for both PP 1– and PP 2A-like activities in the visual and nonvisual tissue of the horseshoe crab, Limulus polyphemus, that membrane and soluble forms of both enzymes are present, and that the activities of both enzymes are greater in light- than in dark-adapted lateral eyes. These activities were characterized using glycogen phosphorylase a, a substrate for both PP 1 and PP 2A, and various protein phosphatase inhibitors, including okadaic acid. We also report that okadaic acid, at concentrations required to inhibit PP 1, inhibited physiological functions of photoreceptor cells from the ventral eye, causing a delayed reduction of the resting membrane, and slowing and reducing light responses.