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PubMedDate not supplied

Evidence for the prolonged photoactivated lifetime of an analogue visual pigment containing 11-cis 9-desmethylretinal.

Following bright flashes, rod photoreceptors exhibit a period of photocurrent saturation that increases linearly with the logarithm of flash intensity. In a recent report, Pepperberg et al. (1992) presented evidence that the slope of the function relating the saturation period (T) to the natural logarithm of flash intensity (ln If) represents the exponential lifetime (tau) of photoactivated visual pigment: tau = delta T/delta [ln If]. In salamander rods, 11-cis 9-desmethylretinal combines with opsin to form 9-desmethyl rhodopsin. Dim flash responses mediated by this analogue visual pigment exhibited slow recovery kinetics relative to those of native pigment (Corson et al., 1991). This observation raises the hypothesis that the physiological lifetime of photoactivated 9-desmethyl rhodopsin is substantially longer than that of native visual pigment. To test this hypothesis, we have examined the relation between the period of photocurrent saturation and flash intensity in salamander rods containing a mixture of the two pigments. Brief stimuli at two widely separated wavelengths (440 and 640 nm) elicited saturating photocurrent responses that were preferentially mediated by 9-desmethyl rhodopsin or residual native pigment, respectively. Plots of T vs. ln If revealed a linear increase in the period of response saturation over a large range of saturating intensities at both wavelengths. However, the slope of the relation between T and ln If with 440-nm flashes was more than twice as large (4.1 +/- 0.5 s, n = 5) as that measured with 640-nm flashes (1.7 +/- 0.4 s). For rods subjected only to bleaching of the native pigment, or to bleaching and resensitization with 11-cis retinal, the slope of the relation between T and ln If remained independent of wavelength and indistinguishable from that of native pigment in unbleached cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2001

Nrl is required for rod photoreceptor development.

The protein neural retina leucine zipper (Nrl) is a basic motif-leucine zipper transcription factor that is preferentially expressed in rod photoreceptors. It acts synergistically with Crx to regulate rhodopsin transcription. Missense mutations in human NRL have been associated with autosomal dominant retinitis pigmentosa. Here we report that deletion of Nrl in mice results in the complete loss of rod function and super-normal cone function, mediated by S cones. The photoreceptors in the Nrl-/- retina have cone-like nuclear morphology and short, sparse outer segments with abnormal disks. Analysis of retinal gene expression confirms the apparent functional transformation of rods into S cones in the Nrl-/- retina. On the basis of these findings, we postulate that Nrl acts as a 'molecular switch' during rod-cell development by directly modulating rod-specific genes while simultaneously inhibiting the S-cone pathway through the activation of Nr2e3.

Animals↗
PubMed1996

Injury-induced remodelling and regeneration of the ribbon presynaptic terminal in vitro.

The neuronal response to axonal injury may relate to the type of insult incurred. Recently, neuritic and presynaptic varicosity regeneration by isolated adult salamander photoreceptors was demonstrated. We have used this system to compare the rod photoreceptor response to two types of injury: denervation/detargeting, the removal of pre- and postsynaptic partners from the axon terminal, and axotomy, the removal of the axon terminal itself. Cells were followed with time-lapse video microscopy for 24-48 h in culture and immunolabelled for SV2 or synaptophysin to identify synaptic vesicle-containing varicosities. Although all injured cells responded with regenerative growth, denervated/detargeted photoreceptors (i.e. neurons which retain their axon terminal) grew 80% more processes and fourfold more presynaptic varicosities than axotomized neurons. In cells which retained their original axon and terminal, varicosity formation generally began with axon retraction. Retraction was followed by elaboration of a lamellipodium and, by 48 h, development of varicosity-bearing neurites from the lamellipodium. Synaptic vesicle protein localization in denervated/detargeted cells paralleled axon terminal reorganization. Axotomized cells, in contrast, lacked synaptic vesicle protein immunoreactivity during this period. To detect synaptic protein synthesis, photoreceptors were examined for colocalization of synaptic vesicle protein with rab6, a Golgi marker, by confocal microscopy. As expected, synaptic vesicle protein staining was present in the Golgi complex during regeneration; however, in cells with an axon, new synaptic vesicle protein-labelled varicosities were found at early stages, prior to the appearance of immunolabel in the Golgi complex. The data demonstrate remarkable plasticity in the ribbon synapse, and suggest that in adult rod cells with an intact axon terminal, synaptic vesicle protein synthesis is not a prerequisite for the formation of new presynaptic-like terminals. We propose that preexisting axonal components are reutilized to expedite presynaptic renewal as an early response to denervation/detargeting.

Ambystoma↗
PubMed2004

STAT3-mediated signaling in the determination of rod photoreceptor cell fate in mouse retina.

PURPOSE: The purpose of this study was to determine the intracellular pathways by which ciliary neurotrophic factor (CNTF) and leukemia inhibitory factor (LIF) negatively regulate the development of rod photoreceptors in the mouse retina. METHODS: Retina explant cultures derived from timed-pregnant CD-1 mice were used to monitor rod photoreceptor differentiation. CNTF was used to activate the signal transducer and activator of transcription (STAT)-3 and mitogen-activated protein kinase (MAPK) signal transduction pathways. Activation of STAT3 and MAPK were manipulated by using dominant-negative STAT3 recombinant adenoviruses and a specific inhibitor of MAPK, respectively. Explanted retinas were harvested at distinct time points and processed for immunohistochemistry. RESULTS: Blocking of the MAPK pathway by the MAPK inhibitor PD98059 did not affect normal development of rods in retina explants or the suppression of their appearance by treatment with CNTF. In contrast, activated STAT3 was necessary for suppression of the rod cell fate decision. A deficiency of the STAT3 pathway induced by a dominant negative STAT3 abolished inhibition of rod development by CNTF. CONCLUSIONS: These results indicate that STAT3, but not MAPK, can critically regulate photoreceptor development during mouse retina development.

Animals↗
PubMed2006

Involvement of Pleiotrophin in CNTF-mediated differentiation of the late retinal progenitor cells.

Ciliary neurotrophic factor (CNTF) participates in retinal development by inhibiting rod differentiation and promoting bipolar and Müller cell differentiation. In order to identify genes which are regulated by CNTF in the developing retina, we carried out a subtractive hybridization study. By this approach, we identified the Pleiotrophin (Ptn) as an upregulated gene in postnatal day 0 (P0) retinal explants upon addition of CNTF. Correlation of overall expression patterns between different retinal cell markers and Ptn in situ hybridization suggest that Ptn transcripts are initially expressed in progenitor cells then in postmitotic precursors of the INL expressing the Chx10 gene, and later in some differentiated retinal Müller glial (RMG) cells and rod-bipolar cells. Overexpression of Ptn by in vitro electroporation of P0 rat retinal explants partially blocks rod differentiation and promotes bipolar cell production, similar to effects of exogenous CNTF and leukemia inhibitory factor (LIF). Furthermore, in P0 retinal explants from mice lacking Ptn, the inhibitory effect of CNTF and LIF on rod differentiation is partially reduced and the cytokine-induced bipolar cell differentiation is largely prevented. Together, these results demonstrate that influence of CNTF family of cytokines on the differentiation of late retinal progenitor cell population is partially mediated by the release of Ptn.

Animals↗
PubMed1998

An isoform of the rod photoreceptor cyclic nucleotide-gated channel beta subunit expressed in olfactory neurons.

Sensory transduction in olfactory neurons involves the activation of a cyclic nucleotide-gated (CNG) channel by cAMP. Previous studies identified a CNG channel alpha subunit (CNG2) and a beta subunit (CNG5), which when heterologously expressed form a channel with properties similar but not identical to those of native olfactory neurons. We have cloned a new type of CNG channel beta subunit (CNG4. 3) from rat olfactory epithelium. CNG4.3 derives from the same gene as the rod photoreceptor beta subunit (CNG4.1) but lacks the long, glutamic acid-rich domain found in the N terminus of CNG4.1. Northern blot and in situ hybridization revealed that CNG4.3 is expressed specifically in olfactory neurons. Expression of CNG4.3 in human embryonic kidney 293 cells did not lead to detectable currents. Coexpression of CNG4.3 with CNG2 induced a current with significantly increased sensitivity for cAMP whereas cGMP affinity was not altered. Additionally, CNG4.3 weakened the outward rectification of the current in the presence of extracellular Ca2+, decreased the relative permeability for Ca2+, and enhanced the sensitivity for L-cis diltiazem. Upon coexpression of CNG2, CNG4.3, and CNG5, a conductance with a cAMP sensitivity greater than that of either the CNG2/CNG4.3 or the CNG2/CNG5 channel and near that of native olfactory channel was observed. Our data suggest that CNG4.3 forms a subunit of the native olfactory CNG channel. The expression of various CNG4 isoforms in retina and olfactory epithelium indicates that the CNG4 subunit may be necessary for normal function of both photoreceptor and olfactory CNG channels.

Amino Acid Sequence↗
PubMed1995

Transient induction of the glial intermediate filament protein gene in Müller cells in the mouse retina.

The glial intermediate filament protein (GFAP) gene is not normally expressed by retinal Müller cells but it is transcriptionally activated following photoreceptor degeneration. In the present study, we have examined the relationship between progressive photoreceptor loss and changes in GFAP gene activity in Müller cells. In albino mice with light-induced photoreceptor degeneration, GFAP level was strongly elevated after 2 weeks. GFAP level remained high even after 3 months in light. In situ hybridization studies showed that GFAP transcripts were quite sparse in the first week but increased dramatically after 2 weeks of light exposure. After 4 weeks in constant light, however, little GFAP mRNA was detected in Müller cells. RNA blotting also showed that there was an approximately 20-fold increase in GFAP mRNA content at 2 weeks; but at 4 weeks, the RNA content fell to about four-fold higher than the basal level. These results show that GFAP level remains high long after its synthesis, probably as a consequence of low GFAP turnover in the Müller cell cytoskeleton, while GFAP mRNA level rises and declines rapidly due to transient activation of the GFAP gene in Müller cells.

Animals↗
PubMed2000

The retinitis pigmentosa GTPase regulator (RPGR) interacts with novel transport-like proteins in the outer segments of rod photoreceptors.

Mutations in the retinitis pigmentosa GTPase regulator (RPGR) gene cause X-linked retinitis pigmentosa type 3 (RP3), a severe, progressive and degenerative retinal dystrophy eventually leading to complete blindness. RPGR is ubiquitously expressed, yet mutations in the RPGR gene lead to a retina-restricted phenotype. To date, all RP3 associated missense mutations that have been identified are located in the RCC1-homologous domain (RHD) of RPGR. To investigate the molecular pathogenesis of RP3, we screened retinal yeast two-hybrid libraries with the RHD of RPGR. We identified several alternatively spliced gene products, some with retina-restricted expression, that interact specifically with RPGR in vivo and in vitro. Thus, these proteins were named RPGR-interacting protein 1 (RPGRIP1) isoforms. They contain a C-terminal RPGR-interacting domain and stretches of variable coiled-coil domains homologous to proteins involved in vesicular trafficking. The interaction between RPGR and RPGRIP1 isoforms was impaired in vivo by RP3-associated mutations in RPGR. Moreover, RPGR and RPGRIP1 co-localize in the outer segment of rod photoreceptors, which is in full agreement with the retinitis pigmentosa phenotype observed in RP3 patients. The localization of RPGRIP1 at 14q11 makes it a strong candidate gene for RP16. These results provide a clue for the retina-specific pathogenesis in RP3, and hint towards the involvement of RPGR and RPGRIP1 in mediating vesicular transport-associated processes.

3' Untranslated Regions↗
PubMed2000

The bHLH gene Hes6, an inhibitor of Hes1, promotes neuronal differentiation.

We have isolated the basic helix-loop-helix (bHLH) gene Hes6, a novel member of the family of mammalian homologues of Drosophila hairy and Enhancer of split. Hes6 is expressed by both undifferentiated and differentiated cells, unlike Hes1, which is expressed only by the former cells. Hes6 alone does not bind to the DNA but suppresses Hes1 from repressing transcription. In addition, Hes6 suppresses Hes1 from inhibiting Mash1-E47 heterodimer and thereby enables Mash1 and E47 to upregulate transcription in the presence of Hes1. Furthermore, misexpression of Hes6 with retrovirus in the developing retina promotes rod photoreceptor differentiation, like Mash1, in sharp contrast to Hes1, which inhibits cell differentiation. These results suggest that Hes6 is an inhibitor of Hes1, supports Mash1 activity and promotes cell differentiation. Mutation analysis revealed that Hes1- and Hes6-specific functions are, at least in part, interchangeable by alteration of the loop region, suggesting that the loop is not simply a nonfunctional spacer but plays an important role in the specific functions.

3T3 Cells↗
PubMed1996

Stochastic simulation of the transducin GTPase cycle.

On rod disc membranes, single photoactivated rhodopsin (R*) molecules catalytically activate many copies of the G-protein (Gt), which in turn binds and activates the effector (phosphodiesterase). We have performed master equation simulations of the underlying diffusional protein interactions on a rectangular 1-micron2 model membrane, divided into 15 x 15 cells. Mono- and bimolecular reactions occur within cells, and diffusional transitions occur between (neighboring) cells. Reaction and diffusion constants yield the related probabilities for the stochastic transitions. The calculated kinetics of active effector form a response that is essentially determined by the stochastic lifetime distribution of R* (with characteristic time tau R*) and the reaction constants of Gt activation. Only a short tau R* (approximately 0.3 s) and a high catalytic rate (3000-4000 Gt s-1 R*-1) are consistent with electrophysiological data. Although R* shut-off limits the rise of the response, the lifetime distribution of free R* is not translated into a corresponding variability of the response peaks, because 1) the lifetime distribution of catalytically engaged R* is distorted, 2) small responses are enlarged by an overshoot of active effector, and 3) larger responses tend to undergo saturation. Comparison of these results to published photocurrent waveforms may open ways to understand the relative uniformity of the rod response.

Animals↗
PubMed2000

Irreversible activation of cyclic nucleotide-gated ion channels by sulfhydryl-reactive derivatives of cyclic GMP.

First discovered in the sensory epithelium of the visual and olfactory systems, cyclic nucleotide-gated (CNG) ion channels have now been found in tissues throughout the body. Native rod CNG channels are tetramers composed of homologous, but distinct, alpha- and beta-subunits. The goal of this study was to develop a novel method for targeting covalent attachment of cGMP to individual subunit types. Toward this goal, we have found that treatment of membrane patches expressing rod alpha-subunit channels with sulfhydryl-reactive derivatives of cGMP resulted in irreversible activation. The persistent currents were sensitive to block by both Mg(2+) and tetracaine. Pretreatment of the patch with the sulfhydryl-blocking reagents N-ethylmaleimide (NEM) and bis-dithionitrobenzoic acid (DTNB) prevented covalent activation; the effect of DTNB was reversed by reduction with DTT. Furthermore, the process of covalent activation was dramatically slowed by the presence of an excess of 8-Br-cGMP. These results suggested that covalent activation resulted from the tethering of cGMP near the channel's ligand-binding sites by reaction with an endogenous cysteine. The alpha-subunit of the rod channel contains seven cysteine residues, and we set out to determine the site of attachment by site-directed mutagenesis. Surprisingly, irreversible activation was not abolished by elimination of all seven cysteine residues. This result suggests that the site of attachment is on a tightly associated protein, rather than on the channel protein itself. To further investigate these results, we treated patches containing irreversibly activated channels with 100 microg/mL trypsin and discovered two modes of covalent activation. One type developed rapidly and was removed by trypsin treatment, and the second developed slowly and was resistant to trypsin treatment. Both types of covalent activation were present in all mutants tested and were also present when CNG channels were expressed in HEK-293 cells. These results suggest that CNG channel subunits may associate with endogenous proteins when they are expressed in heterologous systems.

Affinity Labels↗
PubMed2002

The delta subunit of retinal rod cGMP phosphodiesterase regulates the membrane association of Ras and Rap GTPases.

Post-translational modifications of GTPases from the Ras superfamily enable them to associate with membrane compartments where they exert their biological activities. However, no protein acting like Rho and Rab dissociation inhibitor (GDI) that regulate the membrane association of Rho and Rab GTPases has been described for Ras and closely related proteins. We report here that the delta subunit of retinal rod phosphodiesterase (PDEdelta) is able to interact with prenylated Ras and Rap proteins, and to solubilize them from membranes, independently of their nucleotide-bound (GDP or GTP) state. We show that PDEdelta exhibits striking structural similarities with RhoGDI, namely conservation of the Ig-like fold and presence of a series of hydrophobic residues which could act as in RhoGDI to sequester the prenyl group of its target proteins, thereby providing structural support for the biochemical activity of PDEdelta. We observe that the overexpression of PDEdelta interferes with Ras trafficking and propose that it may play a role in the process that delivers prenylated proteins from endomembranes, once they have undergone proteolysis and carboxymethylation, to the structures that ensure trafficking to their respective resident compartments.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed2002

Non-linear, high-gain and sustained-to-transient signal transmission from rods to amacrine cells in dark-adapted retina of Ambystoma.

In darkness, On-Off amacrine cells (ACs) of the tiger salamander retina exhibited large spontaneous transient depolarizing potentials (sTDPs) with average peak amplitude of 5.05 +/- 2.5 mV and average frequency of 0.42 +/- 0.25 s(-1). Under voltage-clamp conditions the cell displayed large spontaneous postsynaptic currents (sPSCs) with average peak amplitude of 98 +/- 39 pA and average frequency of 0.45 +/- 0.22 s(-1). To a light step, ACs gave rise to a transient 'On' response at the light onset and a transient 'Off' response at light offset, followed by a train of TDPs ('After' response). Near the response threshold (0.3 activated rhodopsin molecules per rod per second), light-evoked TDPs (leTDPs) of similar amplitude and kinetics as the large sTDPs observed in darkness were seen, and about half of these leTDPs elicited a regenerative potential (RP). Brighter light steps gave rise to more leTDPs and higher rates of RPs in the On, Off and After responses. Within the linear response range of the rods, the AC response was non-linear, with the highest gain (676 +/- 429) near the dark potential. The amplitude of Off responses increased with the duration of the light step, and ACs may use this to encode speeds of moving stimuli: the faster the light object moves, the smaller the AC Off response. Moreover, the number of leTDPs in the AC After response increased with light intensity, and the onset of the After response coincides with bipolar cell tail response recovery. One possible origin of the large sTDPs and leTDPs is the spontaneous and depolarization-induced regenerative calcium potentials (RCaPs) in bipolar cell synaptic terminals. RCaPs in bipolar cell synaptic terminals cause transient glutamate release that results in the sTDPs in darkness, and leTDPs in On, Off and After responses in ACs.

Amacrine Cells↗
PubMed1997

Anatomical evidence for rod input to the parvocellular pathway in the visual system of the primate.

The question whether midget bipolar cells in macaque monkey retina receive input from rods was investigated using double-label immunocytochemistry. Flat midget bipolar cells (labelled with antibodies against recoverin) were found to be pre- and postsynaptic to All amacrine cells (labelled with antibodies against calretinin). These results support physiological evidence that rod photoreceptor signals could reach the parvocellular pathway at an early stage of visual processing.

Animals↗
PubMed1998

Expression of the somatostatin subtype 2A receptor in the rabbit retina.

In the retina, somatostatin influences neuronal activity likely by acting at one or more somatostatin subtype (sst) receptors. Somatostatin and somatostatin-binding sites are distributed predominantly to the inner retina. The present study has investigated the cellular expression of one of the sst receptors, the sst2A receptor isoform, in the rabbit retina. These studies have used a new polyclonal antibody directed to the predicted C-terminus of mouse sst2A(361-369) receptor. Antibody specificity was tested by preadsorption of the primary antibody with a peptide corresponding to sst2A(361-369). sst2A Receptor immunoreactivity was localized mainly to the plasma membrane of rod bipolar cells and to sparsely occurring, wide-field amacrine cells. Immunostaining in rod bipolar cells was strongest in the axon and axon terminals in lamina 5 of the inner plexiform layer (IPL) and was weakest in the cell body and dendrites. Double-labeling experiments using a monoclonal antibody against protein kinase C (PKC; alpha and beta), a rod bipolar cell-selective marker, showed complete colocalization. In horizontal sections of retina, immunostained bipolar cell bodies had a dense distribution, which is in agreement with the reported distribution of rod bipolar cell bodies. Immunoreactive amacrine cell bodies were located at the border of the inner nuclear layer and the IPL, and thin varicose processes ramified mainly in laminae 2 and 4 of the IPL. These observations indicate that somatostatin influences visual information processing in the retina 1) by acting presynaptically on rod bipolar cell axon terminals and b) by influencing the activity of sparsely occurring amacrine cells.

Animals↗
PubMed1996

Two classes of bipolar cell in the retina of the skate Raja erinacea.

We have used immunoreactions against serotonin and protein kinase C to visualize two distinct classes of bipolar cell in the all-rod retina of the skate, Raja erinacea. To enhance the immunoreaction in serotonin-accumulating bipolar cells, prior to fixation, some retinas were incubated in Ringer's solution containing serotonin and pargyline. We found the somata of serotonin-accumulating bipolar cells to be located slightly distal to the midline of the inner nuclear layer. With increasing eccentricity from the visual streak, the size of the perikarya increases, concomitant with a decline in density of their distribution. Dendrites emanate from stout primary stalks and branch out before reaching the outer plexiform layer. Axons are bistratified within the inner plexiform layer with ramifications at the border of strata 1 and 2 and in stratum 4. The overall morphology of serotonin-accumulating bipolar cells is similar to that of serotonin-accumulating OFF bipolar cells of other non-mammalian vertebrates. Protein kinase C immunoreactive cells display the typical appearance of rod bipolar cells. Somata of protein kinase C immunoreactive bipolar cells are spindle-shaped and located distal to the serotonin-accumulating bipolar cells. Dendrites of these bipolars do not ramify before reaching the outer plexiform layer. Thin axons of protein kinase C immunoreactive bipolar cells end in large, club-shaped terminals in stratum 5 of the inner plexiform layer, bearing a striking similarity to axon terminals of mammalian ON rod bipolar cells. Our findings suggest that the all-rod retina of the skate contains at least two distinct vertical pathways including an OFF bipolar cell pathway in addition to a classical rod ON bipolar pathway.

Animals↗
PubMed1996

Peripheral colour vision: effects of rod intrusion at different eccentricities.

Chromaticities of monochromatic lights from different parts of the spectrum were measured both during the cone-plateau period of the long-term dark-adaptation curve and in a completely dark-adapted state. The measurements were obtained at 3, 8, 30 and 65 deg in the temporal field of view and at 1, 2, 3 and 4 log units above the cone-plateau level. The results show that cone-mediated colours obtained during the cone-plateau period in general are desaturated when rod signals intrude during long-term dark adaptation. The desaturation effect of rods obtained at high mesopic illumination levels was found to increase when the test field was moved from 3 to 30 deg but to reduce markedly between 30 and 65 deg. Surprisingly, the desaturation was clearly observable even at a retinal illumination of 20,000 ph td. The desaturation effect of rods is explained by the suggestion that differences in ongoing activity rates of the different types of spectrally opponent cells become levelled out to some extent when light signals from rods intrude during dark adaptation.

Color Perception↗