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Experimental Eye Research Nov 2008Human rods and cones are arranged in a precise spatial mosaic that is critical for optimal functioning of the visual system. However, the molecular processes that...
Human rods and cones are arranged in a precise spatial mosaic that is critical for optimal functioning of the visual system. However, the molecular processes that underpin specification of cell types within the mosaic are poorly understood. The progressive differentiation of human rods was tracked from fetal week (Fwk) 9 to postnatal (P) 8 months using immunocytochemical markers of key molecules that represent rod progression from post-mitotic precursors to outer segment-bearing functional photoreceptors. We find two phases associated with rod differentiation. The early phase begins in rods on the foveal edge at Fwk 10.5 when rods are first identified, and the rod-specific proteins NRL and NR2e3 are detected. By Fwk 11-12, these rods label for interphotoreceptor retinoid binding protein, recoverin, and aryl hydrocarbon receptor interacting protein-like 1. The second phase occurs over the next month with the appearance of rod opsin at Fwk 15, closely followed by the outer segment proteins rod GTP-gated sodium channel, rod arrestin, and peripherin. TULP is expressed relatively late at Fwk 18-20 in rods. Each phase proceeds across the retina in a central-peripheral order, such that rods in far peripheral retina are only entering the early phase at the same time that cells in central retina are entering their late phase. During the second half of gestation rods undergo an intracellular reorganization of these proteins, and cellular and OS elongation which continues into infancy. The progression of rod development shown here provides insight into the possible mechanisms underlying human retinal visual dysfunction when there are mutations affecting key rod-related molecules.
Topics: Biomarkers; Cell Differentiation; Eye Proteins; Fetal Development; Gene Expression Regulation, Developmental; Humans; In Situ Hybridization; RNA, Messenger; Retina; Retinal Rod Photoreceptor Cells; Rod Opsins; Vision, Ocular
PubMed: 18778702
DOI: 10.1016/j.exer.2008.07.016 -
The Journal of Biological Chemistry Jun 2023Heat shock protein 90 (HSP90) is an abundant molecular chaperone that regulates the stability of a small set of proteins essential in various cellular pathways....
Heat shock protein 90 (HSP90) is an abundant molecular chaperone that regulates the stability of a small set of proteins essential in various cellular pathways. Cytosolic HSP90 has two closely related paralogs: HSP90α and HSP90β. Due to the structural and sequence similarities of cytosolic HSP90 paralogs, identifying the unique functions and substrates in the cell remains challenging. In this article, we assessed the role of HSP90α in the retina using a novel HSP90α murine knockout model. Our findings show that HSP90α is essential for rod photoreceptor function but was dispensable in cone photoreceptors. In the absence of HSP90α, photoreceptors developed normally. We observed rod dysfunction in HSP90α knockout at 2 months with the accumulation of vacuolar structures, apoptotic nuclei, and abnormalities in the outer segments. The decline in rod function was accompanied by progressive degeneration of rod photoreceptors that was complete at 6 months. The deterioration in cone function and health was a "bystander effect" that followed the degeneration of rods. Tandem mass tag proteomics showed that HSP90α regulates the expression levels of <1% of the retinal proteome. More importantly, HSP90α was vital in maintaining rod PDE6 and AIPL1 cochaperone levels in rod photoreceptor cells. Interestingly, cone PDE6 levels were unaffected. The robust expression of HSP90β paralog in cones likely compensates for the loss of HSP90α. Overall, our study demonstrated the critical need for HSP90α chaperone in the maintenance of rod photoreceptors and showed potential substrates regulated by HSP90α in the retina.
Topics: Animals; Mice; Cyclic Nucleotide Phosphodiesterases, Type 6; HSP90 Heat-Shock Proteins; Retinal Cone Photoreceptor Cells; Retinal Rod Photoreceptor Cells; Protein Subunits; Cell Survival; Gene Expression Regulation, Enzymologic
PubMed: 37172722
DOI: 10.1016/j.jbc.2023.104809 -
BioMed Research International 2018Voltage-gated calcium channels (VGCC) are key to many biological functions. Entry of Ca into cells is essential for initiating or modulating important processes such as... (Review)
Review
Voltage-gated calcium channels (VGCC) are key to many biological functions. Entry of Ca into cells is essential for initiating or modulating important processes such as secretion, cell motility, and gene transcription. In the retina and other neural tissues, one of the major roles of Ca-entry is to stimulate or regulate exocytosis of synaptic vesicles, without which synaptic transmission is impaired. This review will address the special properties of one L-type VGCC, Ca1.4, with particular emphasis on its role in transmission of visual signals from rod and cone photoreceptors (hereafter called "photoreceptors," to the exclusion of intrinsically photoreceptive retinal ganglion cells) to the second-order retinal neurons, and the pathological effects of mutations in the gene which codes for the pore-forming α subunit of Ca1.4.
Topics: Animals; Calcium Channels, L-Type; Humans; Retina; Retinal Cone Photoreceptor Cells; Retinal Rod Photoreceptor Cells; Synaptic Transmission; Vision, Ocular
PubMed: 29854783
DOI: 10.1155/2018/7272630 -
Frontiers in Bioscience : a Journal and... Sep 2002In this review we describe some of the remarkable and intricate mechanisms through which the calcium ion (Ca2+) contributes to detection, transduction and synaptic... (Review)
Review
In this review we describe some of the remarkable and intricate mechanisms through which the calcium ion (Ca2+) contributes to detection, transduction and synaptic transfer of light stimuli in rod and cone photoreceptors. The function of Ca2+ is highly compartmentalized. In the outer segment, Ca2+ controls photoreceptor light adaptation by independently adjusting the gain of phototransduction at several stages in the transduction chain. In the inner segment and synaptic terminal, Ca2+ regulates cells' metabolism, glutamate release, cytoskeletal dynamics, gene expression and cell death. We discuss the mechanisms of Ca2+ entry, buffering, sequestration, release from internal stores and Ca2+ extrusion from both outer and inner segments, showing that these two compartments have little in common with respect to Ca2+ homeostasis. We also investigate the various roles played by Ca2+ as an integrator of intracellular signaling pathways, and emphasize the central role played by Ca2+ as a second messenger in neuromodulation of photoreceptor signaling by extracellular ligands such as dopamine, adenosine and somatostatin. Finally, we review the intimate link between dysfunction in photoreceptor Ca2+ homeostasis and pathologies leading to retinal dysfunction and blindness.
Topics: Adaptation, Physiological; Animals; Calcium; Calcium Channels, L-Type; Calcium Signaling; Ion Channel Gating; Ion Transport; Models, Biological; Photoreceptor Cells, Vertebrate; Retinal Cone Photoreceptor Cells; Retinal Diseases; Retinal Rod Photoreceptor Cells; Vision, Ocular
PubMed: 12161344
DOI: 10.2741/A896 -
The Journal of Physiology Apr 2018Recoverin is a small molecular-weight, calcium-binding protein in rod outer segments that can modulate the rate of rhodopsin phosphorylation. We describe two additional...
KEY POINTS
Recoverin is a small molecular-weight, calcium-binding protein in rod outer segments that can modulate the rate of rhodopsin phosphorylation. We describe two additional and perhaps more important functions during photoreceptor light adaptation. Recoverin influences the rate of change of adaptation. In wild-type rods, sensitivity and response integration time adapt with similar time constants of 150-200 ms. In Rv-/- rods lacking recoverin, sensitivity declines faster and integration time is already shorter and not significantly altered. During steady light exposure, rod circulating current slowly increases during a time course of tens of seconds, gradually extending the operating range of the rod. In Rv-/- rods, this mechanism is deleted, steady-state currents are already larger and rods saturate at brighter intensities. We propose that recoverin modulates spontaneous and light-activated phophodiesterase-6, the phototransduction effector enzyme, to increase sensitivity in dim light but improve responsiveness to change in brighter illumination.
ABSTRACT
Recoverin is a small molecular-weight, calcium-binding protein in rod outer segments that binds to G-protein receptor kinase 1 and can alter the rate of rhodopsin phosphorylation. A change in phosphorylation should change the lifetime of light-activated rhodopsin and the gain of phototransduction, but deletion of recoverin has little effect on the sensitivity of rods either in the dark or in dim-to-moderate background light. We describe two additional functions perhaps of greater physiological significance. (i) When the ambient intensity increases, sensitivity and integration time decrease in wild-type (WT) rods with similar time constants of 150-200 ms. Recoverin is part of the mechanism controlling this process because, in Rv-/- rods lacking recoverin, sensitivity declines more rapidly and integration time is already shorter and not further altered. (ii) During steady light exposure, WT rod circulating current slowly increases during a time course of tens of seconds, gradually extending the operating range of the rod. In Rv-/- rods, this mechanism is also deleted, steady-state currents are already larger and rods saturate at brighter intensities. We argue that neither (i) nor (ii) can be caused by modulation of rhodopsin phosphorylation but may instead be produced by direct modulation of phophodiesterase-6 (PDE6), the phototransduction effector enzyme. We propose that recoverin in dark-adapted rods keeps the integration time long and the spontaneous PDE6 rate relatively high to improve sensitivity. In background light, the integration time is decreased to facilitate detection of change and motion and the spontaneous PDE6 rate decreases to augment the rod working range.
Topics: Adaptation, Physiological; Animals; Cyclic Nucleotide Phosphodiesterases, Type 6; Mice; Mice, Inbred C57BL; Recoverin; Retinal Rod Photoreceptor Cells; Vision, Ocular
PubMed: 29435986
DOI: 10.1113/JP275779 -
Molecular Vision 2009To describe changes induced by retinal detachment in the ultrastructure and organization of rod terminals and their connections with B-type horizontal cell (HC) axon...
PURPOSE
To describe changes induced by retinal detachment in the ultrastructure and organization of rod terminals and their connections with B-type horizontal cell (HC) axon terminals and rod bipolar cell (RB) dendrites.
METHODS
Sections from control, 3 day, 7 day, and 28 day detached feline retinas were prepared for confocal immunofluorescence, light microscopy, and electron microscopy (EM). In addition, 100 mum-thick vibratome sections were immunolabeled with markers for photoreceptor terminals, HCs, and RBs. More than 40 rod spherules were studied in 90 nm-thick serial sections by transmission EM to greater detail changes in their ultrastructure and innervation.
RESULTS
Following retinal detachment, many rod terminals retracted varying distances toward their respective cell bodies in the outer nuclear layer (ONL). In retinas detached for 1 to 4 weeks, an altered synaptic vesicle population and associated ribbons were found in all retracting terminals. Many rod somata in the distal ONL seemed to lack synaptic terminal structures altogether. In a retina detached for 1 week, EM showed that less than half of the retracted terminals remain in contact with RB dendrites. In contrast, almost every surviving spherule was contacted by neurite outgrowths from the axon terminals of the B-type HC. Although retracted spherules had several presynaptic structures similar to those in normal retina, numerous changes occurred in their overall synaptic architecture. The spherule's invagination was shallower, contained fewer postsynaptic processes, and often had "opened," allowing swollen HC processes apposing the synaptic ribbon to directly contact other processes of the outer plexiform layer (OPL) neuropil. Whereas in normal cat retina each HC "lobe" comes from a different axon terminal system, after detachment, the opposing lateral elements can stem from the same terminal. The innervating RB dendrites that branched off stout RB dendritic trunks that extended up into the ONL were thinner than normal, unbranched, often electron dense, and lacked organelles. When present, most merely lay adjacent to retracting spherules rather than enter any synaptic invagination that might still occur.
CONCLUSIONS
Immunocytochemistry enabled RB and HC neurites to appear postsynaptic to retracted rod terminals. However, at the ultrastructural level, HCs seemed to more consistently retain connection with the retracted spherules than the RBs. The highly conserved architecture of the rod spherule was lost as the invagination opened and postsynaptic contacts became fewer. It would seem that the lack of RB central elements as well as the drastic alterations in the architecture of most retracted terminals would necessarily alter the physiology of this complex synapse.
Topics: Animals; Cats; Disease Models, Animal; Immunohistochemistry; Microscopy, Confocal; Models, Biological; Presynaptic Terminals; Retinal Detachment; Retinal Rod Photoreceptor Cells; Synaptic Potentials
PubMed: 19137070
DOI: No ID Found -
The Journal of Neuroscience : the... Aug 2009Retinitis pigmentosa 1 (RP1) is a common inherited retinopathy with variable onset and severity. The RP1 gene encodes a photoreceptor-specific, microtubule-associated...
Retinitis pigmentosa 1 (RP1) is a common inherited retinopathy with variable onset and severity. The RP1 gene encodes a photoreceptor-specific, microtubule-associated ciliary protein containing the doublecortin (DCX) domain. Here we show that another photoreceptor-specific Rp1-like protein (Rp1L1) in mice is also localized to the axoneme of outer segments (OSs) and connecting cilia in rod photoreceptors, overlapping with Rp1. Rp1L1-/- mice display scattered OS disorganization, reduced electroretinogram amplitudes, and progressive photoreceptor degeneration, less severe and slower than in Rp1-/- mice. In single rods of Rp1L1-/-, photosensitivity is reduced, similar to that of Rp1-/-. While individual heterozygotes are normal, double heterozygotes of Rp1 and Rp1L1 exhibit abnormal OS morphology and reduced single rod photosensitivity and dark currents. The electroretinogram amplitudes of double heterozygotes are more reduced than those of individual heterozygotes combined. In support, Rp1L1 interacts with Rp1 in transfected cells and in retina pull-down experiments. Interestingly, phototransduction kinetics are normal in single rods and whole retinas of individual or double Rp1 and Rp1L1 mutant mice. Together, Rp1 and Rp1L1 play essential and synergistic roles in affecting photosensitivity and OS morphogenesis of rod photoreceptors. Our findings suggest that mutations in RP1L1 could underlie retinopathy or modify RP1 disease expression in humans.
Topics: Animals; Axoneme; Doublecortin Protein; Electroretinography; Eye Proteins; Genotype; Kinetics; Mice; Mice, Knockout; Microtubule-Associated Proteins; Photic Stimulation; RNA, Messenger; Retina; Retinal Rod Photoreceptor Cells; Retinitis Pigmentosa; Rhodopsin; Signal Transduction; Vision, Ocular
PubMed: 19657028
DOI: 10.1523/JNEUROSCI.5854-08.2009 -
Physiology (Bethesda, Md.) Feb 2010Photoreceptor cells maintain a roughly constant length by continuously generating new outer segments from their base while simultaneously releasing mature outer segments... (Review)
Review
Photoreceptor cells maintain a roughly constant length by continuously generating new outer segments from their base while simultaneously releasing mature outer segments engulfed by the retinal pigment epithelium (RPE). Thus postmitotic RPE cells phagocytose an immense amount of material over a lifetime, disposing of photoreceptor cell waste while retaining useful content. This review focuses on current knowledge of outer segment phagocytosis, discussing the steps involved along with their critical participants as well as how various perturbations in outer segment (OS) disposal can lead to retinopathies.
Topics: Animals; Humans; Phagocytes; Phagocytosis; Retinal Cone Photoreceptor Cells; Retinal Diseases; Retinal Pigment Epithelium; Retinal Rod Photoreceptor Cells; Signal Transduction
PubMed: 20134024
DOI: 10.1152/physiol.00038.2009 -
The Journal of Physiology Nov 2013We show that various types of rods and cones in the dark-adapted salamander retina are electrically coupled with linear and symmetrical junctional conductances G(j)...
We show that various types of rods and cones in the dark-adapted salamander retina are electrically coupled with linear and symmetrical junctional conductances G(j) (40-223 pS) and a rank order: Rod(C)-large single cone, rod-large single cone, rod-small single cone, rod-accessory double cone and rod-principal double cone. By systematically comparing the transjunctional current-voltage (I(j)-V(j)) relations and average G(j) values of the five types of rod-cone pairs recorded at day and night times, our results suggest that the differences in G(j) values among various types of rod-cone pairs are not caused by circadian differences, and the circadian-dependent changes in rod-cone coupling observed in the fish and rodent retinas are not present in the tiger salamander. In addition to rod-cone coupling, there is a sign-inverting, unidirectional rod→cone current I(RC), and the I(RC)-V(Cone) relations are linear, with a reversal potential near the chloride reversal potential E(Cl). I(RC) can be observed in rods and cones separated by at least 260 μm, and its waveform resembles that of the rod-elicited horizontal cell (HC) response I(HC). A glutamate transporter-associated chloride channel blocker TBOA suppresses I(RC) but not I(HC). These results suggest that I(RC) is largely mediated by HCs via a sign-inverting feedback chemical synapse associated with a chloride channel. I(RC) significantly reduced rod→cone coupling in the frequency range below 15 Hz, allowing better separation of rod and cone signals in the dark-adapted retina.
Topics: Ambystoma; Animals; Circadian Clocks; Dark Adaptation; Light; Photic Stimulation; Photoreceptor Cells, Vertebrate; Retina; Retinal Cone Photoreceptor Cells; Retinal Rod Photoreceptor Cells; Synapses; Synaptic Transmission
PubMed: 24000179
DOI: 10.1113/jphysiol.2013.260984 -
Current Biology : CB Mar 2019Retinal dopamine is released by a specialized subset of amacrine cells in response to light and has a potent influence on how the retina responds to, and encodes, visual...
Retinal dopamine is released by a specialized subset of amacrine cells in response to light and has a potent influence on how the retina responds to, and encodes, visual information. Here, we address the critical question of which retinal photoreceptor is responsible for coordinating the release of this neuromodulator. Although all three photoreceptor classes-rods, cones, and melanopsin-containing retinal ganglion cells (mRGCs)-have been shown to provide electrophysiological inputs to dopaminergic amacrine cells (DACs), we show here that the release of dopamine is defined only by rod photoreceptors. Remarkably, this rod signal coordinates both a suppressive signal at low intensities and drives dopamine release at very bright light intensities. These data further reveal that dopamine release does not necessarily correlate with electrophysiological activity of DACs and add to a growing body of evidence that rods define aspects of retinal function at very bright light levels.
Topics: Amacrine Cells; Animals; Dopamine; Female; Male; Mice; Retinal Rod Photoreceptor Cells
PubMed: 30799247
DOI: 10.1016/j.cub.2019.01.042