Photoreceptor Adaptation Research Articles

Adaptation of Mammalian Photoreceptors to Background Light: Putative Role for Direct Modulation of Phosphodiesterase

All sensory receptors adapt. As the mean level of light or sound or odor is altered, the sensitivity of the receptor is adjusted to permit the cell to function over as wide a range of ambient stimulation as possible. In a rod photoreceptor, adaptation to maintained background light produces a decrease (or "sag") in the response to the prolonged illumination, as well as an acceleration in response decay time and a Weber-Fechner-like decrease in sensitivity. Earlier work on salamander indicated that adaptation is controlled by the intracellular concentration of Ca(2+). Three Ca(2+)-dependent mechanisms were subsequently identified, namely, regulation of guanylyl cyclase, modulation of activated rhodopsin lifetime, and alteration of channel opening probability, with the contribution of the cyclase thought to be the most important. Later experiments on mouse that exploit the powerful techniques of molecular genetics have shown that cyclase does indeed play a significant role in mammalian rods, but that much of adaptation remains even when regulation of cyclase and both of the other proposed pathways have been genetically deleted. The identity of the missing mechanism or mechanisms is unclear, but recent speculation has focused on direct modulation of spontaneous and light-activated phosphodiesterase.

Variation in Rhodopsin Kinase Expression Alters the Dim Flash Response Shut Off and the Light Adaptation in Rod Photoreceptors

Rod photoreceptors are exquisitely sensitive light detectors that function in dim light. The timely inactivation of their light responses is critical for the ability of rods to reliably detect and count photons. A key step in the inactivation of the rod transduction is the phosphorylation of the rod visual pigment, rhodopsin, catalyzed by G-protein-dependent receptor kinase 1 (GRK1). Absence of GRK1 greatly prolongs the photoreceptors' light response and enhances their susceptibility to degeneration. This study examined the light responses from mouse rods expressing various levels of GRK1 to evaluate how their function is modulated by rhodopsin inactivation. Transretinal and single-cell rod electrophysiological recordings were obtained from several strains of mice expressing GRK1 at 0.3- to 3-fold the wild-type levels. The effect of GRK1 expression level on the function of mouse rods was examined in darkness and during background adaptation. Altering the expression of GRK1 from 0.3- to 3-fold that in wild-type rods had little effect on the single photon response amplitude. Notably, increasing the expression level of GRK1 accelerated the dim flash response shut off but had no effect on the saturated response shut off. Additionally, GRK1 excess abolished the acceleration of saturated responses shut off during light adaptation. These results demonstrate that rhodopsin inactivation can modulate the kinetics of recovery from dim light stimulation. More importantly, the ratio of rhodopsin kinase to its modulator recoverin appears critical for the proper adaptation of rods and the acceleration of their response shut off in background light.

Characterization of the Oligomeric Structure of the Ca2+-activated Cl− Channel Ano1/TMEM16A

Members of the Anoctamin (Ano)/TMEM16A family have recently been identified as essential subunits of the Ca(2+)-activated chloride channel (CaCC). For example, Ano1 is highly expressed in multiple tissues including airway epithelia, where it acts as an apical conduit for transepithelial Cl(-) secretion and helps regulate lung liquid homeostasis and mucus clearance. However, little is known about the oligomerization of this protein in the plasma membrane. Thus, utilizing mCherry- and eGFP-tagged Ano1 constructs, we conducted biochemical and Förster resonance energy transfer (FRET)-based experiments to determine the quaternary structure of Ano1. FRET and co-immunoprecipitation studies revealed that tagged Ano1 subunits directly associated before they reached the plasma membrane. This association was not altered by changes in cytosolic Ca(2+), suggesting that this is a fixed interaction. To determine the oligomeric structure of Ano1, we performed chemical cross-linking, non-denaturing PAGE, and electromobility shift assays, which revealed that Ano1 exists as a dimer. These data are the first to probe the quaternary structure of Ano1. Understanding the oligomeric nature of Ano1 is an essential step in the development of therapeutic drugs that could be useful in the treatment of cystic fibrosis.

Diffusion and light-dependent compartmentalization of transducin

Diffusion and light-dependent compartmentalization of transducin are essential for phototransduction and light adaptation of rod photoreceptors. Here, transgenic Xenopus laevis models were designed to probe the roles of transducin/rhodopsin interactions and lipid modifications in transducin compartmentalization, membrane mobility, and light-induced translocation. Localization and diffusion of EGFP-fused rod transducin-α subunit (Gαt1), mutant Gαt1 that is predicted to be N-acylated and S-palmitoylated (Gαt1A3C), and mutant Gαt1 uncoupled from light-activated rhodopsin (Gαt1-Ctαs), were examined by EGFP-fluorescence imaging and fluorescence recovery after photobleaching (FRAP). Similar to Gαt1, Gαt1A3C and Gαt1-Ctαs were correctly targeted to the rod outer segments in the dark, however the light-dependent translocation of both mutants was markedly impaired. Our analysis revealed a moderate acceleration of the lateral diffusion for the activated Gαt1 consistent with the diffusion of the separated Gαt1GTP and Gβ1γ1 on the membrane surface. Unexpectedly, the kinetics of longitudinal diffusion were comparable for Gαt1GTP with a single lipid anchor and heterotrimeric Gαt1β1γ1 or Gαt1-Ctαsβ1γ1 with two lipid modifications. This contrasted the lack of the longitudinal diffusion of the Gαt1A3C mutant apparently caused by its stable two lipid attachment to the membrane and suggests the existence of a mechanism that facilitates axial diffusion of Gαt1β1γ1.

Visual physiology underlying orientation and diel behavior in the sand beach amphipod Talorchestia longicornis

Talitrid amphipods employ vision for zonal recovery behaviors on sand beaches and for entraining circadian activity rhythms. Using a hierarchy of methods, we examined visual spectral and response-intensity functions in Talorchestia longicornis, a species in which orientation and rhythm entrainment are wavelength-specific behaviors. Microspectrophotometry, electroretinogram recording and behavioral assays were used to determine visual pigments, retinal spectral sensitivity and whole-animal spectral responsivity, respectively. Diel changes in absolute sensitivity were also investigated at retinal and whole-animal levels. Two receptor spectral classes were identified, with values for visual pigment λ(max) of 427 and 518 nm. Retinal spectral sensitivity varied with electrode position along the distal-proximal axis. Chromatic adaptation of distal and proximal photoreceptors resulted in sensitivity peaks at 430 and 522 nm, respectively. In accordance with identified visual pigments and spectral sensitivity, T. longicornis photobehavioral responsivity covered a broad range (420-580 nm). Collectively, a dual-pigment visual system underlies wavelength-specific behavior in T. longicornis, with the short-wavelength pigment likely to be localized in the distal R5 retinular cell. While response-intensity functions did not change over the diel cycle at the retinal level, behavioral photoresponsiveness varied between day and night. At a wavelength used by T. longicornis for celestial orientation (420 nm), photobehavior was heightened at night, potentially aiding in nocturnal orientation. By contrast, at a wavelength used to entrain its circadian rhythm (520 nm) and for routine visual tasks, photobehavior was heightened during the day, and spectral sensitivity matched to the twilight spectrum, facilitating crepuscular vision and entrainment by irradiance at sunrise and sunset.

A Model to Study Effect of Rapid Buffers and Na+ on Ca2+ Oscillations in Neuron Cell

$Ca^{2+}$ plays a vital role in muscle mechanics, cardiacelectrophysiology, secretion, hair cells, and adaptation inphotoreceptors. It is a vital second messenger used in signaltransduction. Calcium controls cell movement, cell differentiation,ciliary beating. Many cells exhibit oscillations in intracellular[Ca$^{2+}$] in response to agonist such as hormones andneurotransmitters. Many cells use oscillations in calciumconcentration to transmit messages (Sneyd J. et al, 2006, p.151-163). In this paper, an attempt has been made to develop a modelto study calcium oscillations in neuron cells. This modelincorporates the effect of variable Na$^{+}$ influx, sodium-calciumexchange (NCX) protein, Sarcolemmal Calcium ATPase (SL) pump,Sarco-Endoplasmic Reticulum CaATPase (SERCA) pump, sodium andcalcium channels, and $IP_{3}R$ channel. The proposed mathematicalmodel leads to a system of partial differential equations which hasbeen solved numerically using Forward Time Centered Space (FTCS)approach. The numerical results have been used to study therelationships among different types of parameters such as bufferconcentration, disassociation rate, calcium permeability, etc.

Responses to Static Visual Images in Macaque Lateral Geniculate Nucleus: Implications for Adaptation, Negative Afterimages, and Visual Fading

Adaptation to static scenes is a familiar and fundamental aspect of visual perception that causes negative afterimages, fading, and many other visual illusions. To establish a foundation for understanding the neuronal bases of such phenomena and to constrain the contributions of retinal versus cortical processing, we studied the responses of neurons in the dorsal lateral geniculate nucleus during and after the presentation of prolonged static visual stimuli. We found that parvocellular (P) cells (the more numerous and color-sensitive pathway) showed response adaptation with a time constant on the order of tens of seconds and that their response after the removal of a visual stimulus lasting 1 min was similar in amplitude and time course to the response evoked by the photographic negative stimulus. Magnocellular (M) cells (the faster-conducting and achromatic pathway) had after responses that were substantially weaker than responses evoked by patterned visual stimuli. This difference points to the existence of an adaptive mechanism in the P-pathway that is absent or impaired in the M-pathway and is inconsistent with full adaptation of photoreceptors, which feed both pathways. Cells in both pathways often maintained a substantial tonic response throughout 1 min stimuli, suggesting that these major feedforward inputs to cortex adapt too slowly to account for visual fading. Our findings suggest that faster-adapting mechanisms in cortex are likely to be required to account for the dynamics of perception during and after the viewing of prolonged static images.

Prolonged illumination up‐regulates arrestin and two guanylate cyclase activating proteins: a novel mechanism for light adaptation

Light adaptation in vertebrate photoreceptors is mediated by multiple mechanisms, one of which could involve nuclear feedback and changes in gene expression. Therefore, we have investigated light adaptation-associated changes in gene expression using microarrays and real-time PCR in isolated photoreceptors, in cultured isolated retinas and in acutely isolated retinas. In all three preparations after 2 h of an exposure to a bright light, we observed an up-regulation of almost 100% of three genes, Sag, Guca1a and Guca1b, coding for proteins known to play a major role in phototransduction: arrestin, GCAP1 and GCAP2. No detectable up-regulation occurred for light exposures of less than 1 h. Functional in vivo electroretinographic tests show that a partial recovery of the dark current occurred 1-2 h after prolonged illumination with a steady light that initially caused a substantial suppression of the photoresponse. These observations demonstrate that prolonged illumination results in the up-regulation of genes coding for proteins involved in the phototransduction signalling cascade, possibly underlying a novel component of light adaptation occurring 1-2 h after the onset of a steady bright light.

Light-Dependent Translocation of Arrestin in Rod Photoreceptors is Signaled through a Phospholipase C Cascade and Requires ATP

Light adaptation of rod photoreceptors induces translocation of arrestin from inner segments (IS) to outer segments (OS). Our study suggests that components of the G-protein linked phosphoinositide pathway play a role in signaling the initiating events of arrestin translocation. We show that arrestin translocation can be stimulated by activators of phospholipase C (PLC) and protein kinase C (PKC) in the absence of light. Conversely, arrestin translocation to the OS is significantly slowed by inhibitors of PLC and PKC.

The translocation of signaling molecules in dark adapting mammalian rod photoreceptor cells is dependent on the cytoskeleton

In vertebrate rod photoreceptor cells, arrestin and the visual G-protein transducin move between the inner segment and outer segment in response to changes in light. This stimulus dependent translocation of signalling molecules is assumed to participate in long term light adaptation of photoreceptors. So far the cellular basis for the transport mechanisms underlying these intracellular movements remains largely elusive. Here we investigated the dependency of these movements on actin filaments and the microtubule cytoskeleton of photoreceptor cells. Co-cultures of mouse retina and retinal pigment epithelium were incubated with drugs stabilizing and destabilizing the cytoskeleton. The actin and microtubule cytoskeleton and the light dependent distribution of signaling molecules were subsequently analyzed by light and electron microscopy. The application of cytoskeletal drugs differentially affected the cytoskeleton in photoreceptor compartments. During dark adaptation the depolymerization of microtubules as well as actin filaments disrupted the translocation of arrestin and transducin in rod photoreceptor cells. During light adaptation only the delivery of arrestin within the outer segment was impaired after destabilization of microtubules. Movements of transducin and arrestin required intact cytoskeletal elements in dark adapting cells. However, diffusion might be sufficient for the fast molecular movements observed as cells adapt to light. These findings indicate that different molecular translocation mechanisms are responsible for the dark and light associated translocations of arrestin and transducin in rod photoreceptor cells.

Visual Reliability and Information Rate in the Retina of a Nocturnal Bee

Nocturnal animals relying on vision typically have eyes that are optically and morphologically adapted for both increased sensitivity and greater information capacity in dim light. Here, we investigate whether adaptations for increased sensitivity also are found in their photoreceptors by using closely related and fast-flying nocturnal and diurnal bees as model animals. The nocturnal bee Megalopta genalis is capable of foraging and homing by using visually discriminated landmarks at starlight intensities. Megalopta's near relative, Lasioglossum leucozonium, performs these tasks only in bright sunshine. By recording intracellular responses to Gaussian white-noise stimuli, we show that photoreceptors in Megalopta actually code less information at most light levels than those in Lasioglossum. However, as in several other nocturnal arthropods, Megalopta's photoreceptors possess a much greater gain of transduction, indicating that nocturnal photoreceptors trade information capacity for sensitivity. By sacrificing photoreceptor signal-to-noise ratio and information capacity in dim light for an increased gain and, thus, an increased sensitivity, this strategy can benefit nocturnal insects that use neural summation to improve visual reliability at night.

Somatostatin Peptides Produce Multiple Effects on Gating Properties of Native Cone Photoreceptor cGMP-Gated Channels That Depend on Circadian Phase and Previous Illumination

A subpopulation of avian amacrine cells expresses somatostatin-14 (SS14) and somatostatin-28 (SS28), which provide a potential efferent limb for light-dependent regulation of photoreceptors. Here, we demonstrate that SS14 and SS28 modulate cone photoreceptor cGMP-gated channels (CNGCs) through multiple mechanisms. In chicken cones cultured in constant darkness for 2 d after previous entrainment to light-dark (LD) cycles or in cells maintained in LD, application of 100 nm SS14 or 100 nm SS28 for either 15 min or 2 h caused a decrease in the sensitivity of CNGCs to cGMP during the night, at circadian time 16 (CT16)-CT20 or zeitgeber time 16 (ZT16)-ZT20. SS14 had no effect during the day (CT4-CT8 or ZT4-ZT8). These effects persist in cells pretreated with pertussis toxin (PTX) and, like dopamine, may work to reinforce long-term circadian fluctuations in CNGCs driven by oscillators within the photoreceptors themselves. In contrast, a 15 min exposure to SS28 caused a seemingly paradoxical increase in the sensitivity of CNGCs to cGMP during the early day (ZT4-ZT6), but only in cones maintained in LD. This effect of SS28 desensitizes rapidly, is blocked by pretreatment with PTX, and is selectively mimicked by the cyclohexapeptide agonist MK-678. This transient response also requires activation of phospholipase C and protein kinase C. The transient response to SS28 may play a role in photoreceptor adaptation to rapid changes in ambient illumination. These data also show that photoreceptor responses to at least some peptide neurotransmitters depend on the previous history of light exposure.

Na+/Ca2+ exchangers: three mammalian gene families control Ca2+ transport

Mammalian Na+/Ca2+ exchangers are members of three branches of a much larger family of transport proteins [the CaCA (Ca2+/cation antiporter) superfamily] whose main role is to provide control of Ca2+ flux across the plasma membranes or intracellular compartments. Since cytosolic levels of Ca2+ are much lower than those found extracellularly or in sequestered stores, the major function of Na+/Ca2+ exchangers is to extrude Ca2+ from the cytoplasm. The exchangers are, however, fully reversible and thus, under special conditions of subcellular localization and compartmentalized ion gradients, Na+/Ca2+ exchangers may allow Ca2+ entry and may play more specialized roles in Ca2+ movement between compartments. The NCX (Na+/Ca2+ exchanger) [SLC (solute carrier) 8] branch of Na+/Ca2+ exchangers comprises three members: NCX1 has been most extensively studied, and is broadly expressed with particular abundance in heart, brain and kidney, NCX2 is expressed in brain, and NCX3 is expressed in brain and skeletal muscle. The NCX proteins subserve a variety of roles, depending upon the site of expression. These include cardiac excitation-contraction coupling, neuronal signalling and Ca2+ reabsorption in the kidney. The NCKX (Na2+/Ca2+-K+ exchanger) (SLC24) branch of Na+/Ca2+ exchangers transport K+ and Ca2+ in exchange for Na+, and comprises five members: NCKX1 is expressed in retinal rod photoreceptors, NCKX2 is expressed in cone photoreceptors and in neurons throughout the brain, NCKX3 and NCKX4 are abundant in brain, but have a broader tissue distribution, and NCKX5 is expressed in skin, retinal epithelium and brain. The NCKX proteins probably play a particularly prominent role in regulating Ca2+ flux in environments which experience wide and frequent fluctuations in Na+ concentration. Until recently, the range of functions that NCKX proteins play was generally underappreciated. This situation is now changing rapidly as evidence emerges for roles including photoreceptor adaptation, synaptic plasticity and skin pigmentation. The CCX (Ca2+/cation exchanger) branch has only one mammalian member, NCKX6 or NCLX (Na+/Ca2+-Li+ exchanger), whose physiological function remains unclear, despite a broad pattern of expression.

Pushing it to the Limit: Adaptation with Dynamically Switching Gain Control

With this paper we propose a model to simulate the functional aspects of light adaptation in retinal photoreceptors. Our model, however, does not link specific stages to the detailed molecular processes which are thought to mediate adaptation in real photoreceptors. We rather model the photoreceptor as a self-adjusting integration device, which adds up properly amplified luminance signals. The integration process and the amplification obey a switching behavior that acts to locally shut down the integration process in dependence on the internal state of the receptor. The mathematical structure of our model is quite simple, and its computational complexity is quite low. We present results of computer simulations which demonstrate that our model adapts properly to at least four orders of input magnitude.

Phase and Period Responses of the Circadian System of Mice (Mus musculus) to Light Stimuli of Different Duration

To understand entrainment of circadian systems to different photoperiods in nature, it is important to know the effects of single light pulses of different durations on the free-running system. The authors studied the phase and period responses of laboratory mice (C57BL6J//OlaHsd) to single light pulses of 7 different durations (1, 3, 4, 6, 9, 12, and 18 h) given once per 11 days in otherwise constant darkness. Light-pulse duration affected both amplitude and shape of the phase response curve. Nine-hour light pulses yielded the maximal amplitude PRC. As in other systems, the circadian period slightly lengthened following delays and shortened following advances. The authors aimed to understand how different parts of the light signal contribute to the eventual phase shift. When PRCs were plotted using the onset, midpoint, and end of the pulse as a phase reference, they corresponded best with each other when using the mid-pulse. Using a simple phase-only model, the authors explored the possibility that light affects oscillator velocity strongly in the 1st hour and at reduced strength in later hours of the pulse due to photoreceptor adaptation. They fitted models based on the 1-h PRC to the data for all light pulses. The best overall correspondence between PRCs was obtained when the effect of light during all hours after the first was reduced by a factor of 0.22 relative to the 1st hour. For the predicted PRCs, the light action centered on average at 38% of the light pulse. This is close to the reference phase yielding best correspondence at 36% of the pulses. The result is thus compatible with an initial major contribution of the onset of the light pulse followed by a reduced effect of light responsible for the differences between PRCs for different duration pulses. The authors suggest that the mid-pulse is a better phase reference than lights-on to plot and compare PRCs of different light-pulse durations.

Measuring room illuminance

In the article by Wickremasinghe et al.,1 we are concerned by Figure 3 (mean pupil diameter [PD] versus illumination in lux), which would predict a mean PD at 1 lux of approximately 4.5 mm in a study population with a mean age of 38 years. Our work2 shows a mean dark-adapted PD (DAPD) of approximately 7.0 mm in a similar population. A discrepancy of 2.5 mm requires an explanation. Reading the Methods section with care, we noted that there was no preadaptation step, which we have found important in accelerating low-light adaptation once the patient enters the testing room (unpublished data); the duration of subsequent low-light adaptation was also variable. However, our greatest concern was with the measurement of ambient illumination. The investigators used the Sixtomat digital photographic exposure meter (Gossen AG) to allegedly adjust the ambient illumination in their testing room to 0.08 lux. When we perused a digital version of the Sixtomat's technical data sheet and user's manual (English translation) from Gossen's Web page, we did not see a clear indication that this device could function as an illuminance meter with a readout in lux. We contacted Gossen AG and received the following reply, quoted without modification, via e-mail from Gudrun Zeller, Export Area Manager: “Please note that the Sixtomat Digital is a light meter for photography, for ambient light and shows EV, f-stops, exp. times, etc. There is no indication of lux since this meter is not designed to measure illuminance but to assist in making perfect photos.” Our own research has been challenged on the grounds that our light measurement system was both imprecise and inaccurate (Daniel Taylor, Procyon, UK, personal communication). We used the AEMC CA813 illuminance meter (AEMC Instruments), which is calibrated to the spectral sensitivity of the human eye. This meter has a display precision of 0.01 lux, but for purposes of honest realism, we adjusted the ambient illumination to 1 lux (not 1.0 or 1.00 lux). At very low light levels, slight changes in reflected light caused by movement of the examiner or patient will cause variability in the luxmeter reading. When read to 1 decimal place, our “1 lux” ranged between 0.8 and 1.4 lux; this range corresponds with a “very-low-mesopic” level of retinal photoreceptor adaptation in which the rod system is fully active but some color information is retained because there is sufficient light to stimulate cones with low frequency. Tiny differences in low-level illumination (eg, 0.04 lux versus 0.4 lux) are of no practical importance under ordinary low-light activities of daily living. We agree with Wickremasinghe et al.1 that evaluation of the DAPD is a crucial portion of the preoperative refractive surgery workup and hope that future studies will address all conditions needed for accurate DAPD measurement. Regrettably, we see no way in which their study can be salvaged and we feel that clinicians should not use the reported findings as the basis for surgical decision making.

Photoreceptor Adaptation in Intrinsically Photosensitive Retinal Ganglion Cells

A rare type of mammalian retinal ganglion cell (RGC) expresses the photopigment melanopsin and is a photoreceptor. These intrinsically photosensitive RGCs (ipRGCs) drive circadian-clock resetting, pupillary constriction, and other non-image-forming photic responses. Both the light responses of ipRGCs and the behaviors they drive are remarkably sustained, raising the possibility that, unlike rods and cones, ipRGCs do not adjust their sensitivity according to lighting conditions ("adaptation"). We found, to the contrary, that ipRGC sensitivity is plastic, strongly influenced by lighting history. When exposed to a constant, bright background, the background-evoked response decayed, and responses to superimposed flashes grew in amplitude, indicating light adaptation. After extinction of a light-adapting background, sensitivity recovered progressively in darkness, indicating dark adaptation. Because these adjustments in sensitivity persisted when synapses were blocked, they constitute "photoreceptor adaptation" rather than "network adaptation." Implications for the mechanisms generating various non-image-forming visual responses are discussed.

Transducin Activation State Controls Its Light-dependent Translocation in Rod Photoreceptors

Light-dependent redistribution of transducin between the rod outer segments (OS) and other photoreceptor compartments including the inner segments (IS) and synaptic terminals (ST) is recognized as a critical contributing factor to light and dark adaptation. The mechanisms of light-induced transducin translocation to the IS/ST and its return to the OS during dark adaptation are not well understood. We have probed these mechanisms by examining light-dependent localizations of the transducin-alpha subunit (Gtalpha)in mice lacking the photoreceptor GAP-protein RGS9, or expressing the GTPase-deficient mutant GtalphaQ200L. An illumination threshold for the Gtalpha movement out of the OS is lower in the RGS9 knockout mice, indicating that the fast inactivation of transducin in the wild-type mice limits its translocation to the IS/ST. Transgenic GtalphaQ200L mice have significantly diminished levels of proteins involved in cGMP metabolism in rods, most notably the PDE6 catalytic subunits, and severely reduced sensitivity to light. Similarly to the native Gtalpha, the GtalphaQ200L mutant is localized to the IS/ST compartment in light-adapted transgenic mice. However, the return of GtalphaQ200L to the OS during dark adaptation is markedly slower than normal. Thus, the light-dependent translocations of transducin are controlled by the GTP-hydrolysis on Gtalpha, and apparently, do not require Gtalpha interaction with RGS9 and PDE6.

Extreme hyperopia is the result of null mutations inMFRP, which encodes a Frizzled-related protein

Nanophthalmos is a rare disorder of eye development characterized by extreme hyperopia (farsightedness), with refractive error in the range of +8.00 to +25.00 diopters. Because the cornea and lens are normal in size and shape, hyperopia occurs because insufficient growth along the visual axis places these lensing components too close to the retina. Nanophthalmic eyes show considerable thickening of both the choroidal vascular bed and scleral coat, which provide nutritive and structural support for the retina. Thickening of these tissues is a general feature of axial hyperopia, whereas the opposite occurs in myopia. We have mapped recessive nanophthalmos to a unique locus at 11q23.3 and identified four independent mutations in MFRP, a gene that is selectively expressed in the eye and encodes a protein with homology to Tolloid proteases and the Wnt-binding domain of the Frizzled transmembrane receptors. This gene is not critical for retinal function, as patients entirely lacking MFRP can still have good refraction-corrected vision, produce clinically normal electro-retinograms, and show only modest anomalies in the dark adaptation of photoreceptors. MFRP appears primarily devoted to regulating axial length of the eye. It remains to be determined whether natural variation in its activity plays a role in common refractive errors.

Calcium-Independent, cGMP-Mediated Light Adaptation in Invertebrate Ciliary Photoreceptors

Calcium is thought to be essential for adaptation of sensory receptor cells. However, the transduction cascade of hyperpolarizing, ciliary photoreceptors of the scallop does not use IP3-mediated Ca release, and the light-sensitive conductance is not measurably permeable to Ca2+. Therefore, two typical mechanisms that couple the light response to [Ca]i changes seem to be lacking in these photoreceptors. Using fluorescent indicators, we determined that, unlike in their microvillar counterparts, photostimulation of ciliary cells under voltage clamp indeed evokes no detectable change in cytosolic Ca. Notwithstanding, these cells exhibit all of the hallmarks of light adaptation, including response range compression, sensitivity shift, and photoresponse acceleration. A possible mediator of Ca-independent sensory adaptation is cGMP, the second messenger that regulates the light-sensitive conductance; cGMP and 8-bromo cGMP not only activate light-dependent K channels but also reduce the amplitude of the light response to an extent greatly in excess of that expected from simple occlusion between light and chemical stimulation. In addition, these substances accelerate the time course of the photocurrent. Tests with pharmacological antagonists suggest that protein kinase G may be a downstream effector that controls, in part, the cGMP-triggered changes in photoresponse properties during light adaptation. However, additional messengers are likely to be implicated, especially in the regulation of response kinetics. These observations suggest a novel feedback inhibition pathway for signaling sensory adaptation.