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Article ; Online: Pig Models in Retinal Research and Retinal Disease.

McCall, Maureen A

Cold Spring Harbor perspectives in medicine

2024 Volume 14, Issue 4

Abstract: The pig has been used as a large animal model in biomedical research for many years and its use continues to increase because induced mutations phenocopy several inherited human diseases. In addition, they are continuous breeders, can be propagated by ... ...

Abstract	The pig has been used as a large animal model in biomedical research for many years and its use continues to increase because induced mutations phenocopy several inherited human diseases. In addition, they are continuous breeders, can be propagated by artificial insemination, have large litter sizes (on the order of mice), and can be genetically manipulated using all of the techniques that are currently available in mice. The pioneering work of Petters and colleagues set the stage for the use of the pig as a model of inherited retinal disease. In the last 10 years, the pig has become a model of choice where specific disease-causing mutations that are not phenocopied in rodents need to be studied and therapeutic approaches explored. The pig is not only used for retinal eye disease but also for the study of the cornea and lens. This review attempts to show how broad the use of the pig has become and how it has contributed to the assessment of treatments for eye disease. In the last 10 years, there have been several reviews that included the use of the pig in biomedical research (see body of the review) that included information about retinal disease. None directly discuss the use of the pig as an animal model for retinal diseases, including inherited diseases, where a single genetic mutation has been identified or for multifactorial diseases such as glaucoma and diabetic retinopathy. Although the pig is used to explore diseases of the cornea and lens, this review focuses on how and why the pig, as a large animal model, is useful for research in neural retinal disease and its treatment.
MeSH term(s)	Animals ; Disease Models, Animal ; Models, Animal ; Mutation ; Phenotype ; Retina ; Retinal Diseases/genetics ; Retinal Diseases/therapy ; Swine
Language	English
Publishing date	2024-04-01
Publishing country	United States
Document type	Journal Article ; Review
ISSN	2157-1422
ISSN (online)	2157-1422
DOI	10.1101/cshperspect.a041296
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Article ; Online: Binocular benefit following monocular subretinal AAV injection in a mouse model of autosomal dominant retinitis pigmentosa (adRP).

Ahmed, Chulbul M / Massengill, Michael T / Ildefonso, Cristhian J / Jalligampala, Archana / Zhu, Ping / Li, Hong / Patel, Anil P / McCall, Maureen A / Lewin, Alfred S

Vision research

2023 Volume 206, Page(s) 108189

Abstract: Autosomal dominant retinitis pigmentosa (adRP) is frequently caused by mutations in RHO, the gene for rhodopsin. In previous experiments in dogs with the T4R mutation in RHO, an AAV2/5 vector expressing an shRNA directed to human and dog RHO mRNA and an ... ...

Abstract	Autosomal dominant retinitis pigmentosa (adRP) is frequently caused by mutations in RHO, the gene for rhodopsin. In previous experiments in dogs with the T4R mutation in RHO, an AAV2/5 vector expressing an shRNA directed to human and dog RHO mRNA and an shRNA-resistant human RHO cDNA (AAV-RHO820-shRNA820) prevented retinal degeneration for more than eight months following injection. It is crucial, however, to determine if this RNA replacement vector acts in a mutation-independent and species-independent manner. We, therefore, injected mice transgenic for human P23H RHO with this vector unilaterally at postnatal day 30. We monitored their retinal structure by using spectral-domain optical coherence tomography (SD-OCT) and retinal function using electroretinography (ERG) for nine months. We compared these to P23H RHO transgenic mice injected unilaterally with a control vector. Though retinas continued to thin over time, compared to control injected eyes, treatment with AAV-RHO820-shRNA820 slowed the loss of photoreceptor cells and the decrease in ERG amplitudes during the nine-month study period. Unexpectedly, we also observed the preservation of retinal structure and function in the untreated contralateral eyes of AAV-RHO820-shRNA820 treated mice. PCR analysis and western blots showed that a low amount of vector from injected eyes was present in uninjected eyes. In addition, protective neurotrophic factors bFGF and GDNF were elevated in both eyes of treated mice. Our finding suggests that using this or similar RNA replacement vectors in human gene therapy may provide clinical benefit to both eyes of patients with adRP.
MeSH term(s)	Humans ; Mice ; Animals ; Dogs ; Retinitis Pigmentosa/genetics ; Retinitis Pigmentosa/therapy ; Retina ; Rhodopsin/genetics ; Electroretinography ; Mice, Transgenic ; RNA, Small Interfering ; Disease Models, Animal
Chemical Substances	Rhodopsin (9009-81-8) ; RNA, Small Interfering
Language	English
Publishing date	2023-02-09
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	200427-6
ISSN	1878-5646 ; 0042-6989
ISSN (online)	1878-5646
ISSN	0042-6989
DOI	10.1016/j.visres.2023.108189
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Article ; Online: Gain control by sparse, ultra-slow glycinergic synapses.

Jain, Varsha / Hanson, Laura / Sethuramanujam, Santhosh / Michaels, Tracy / Gawley, Jerram / Gregg, Ronald G / Pyle, Ian / Zhang, Chi / Smith, Robert G / Berson, David / McCall, Maureen A / Awatramani, Gautam B

Cell reports

2022 Volume 38, Issue 8, Page(s) 110410

Abstract: In the retina, ON starburst amacrine cells (SACs) play a crucial role in the direction-selective circuit, but the sources of inhibition that shape their response properties remain unclear. Previous studies demonstrate that ∼95% of their inhibitory ... ...

Abstract	In the retina, ON starburst amacrine cells (SACs) play a crucial role in the direction-selective circuit, but the sources of inhibition that shape their response properties remain unclear. Previous studies demonstrate that ∼95% of their inhibitory synapses are GABAergic, yet we find that the light-evoked inhibitory currents measured in SACs are predominantly glycinergic. Glycinergic inhibition is extremely slow, relying on non-canonical glycine receptors containing α4 subunits, and is driven by both the ON and OFF retinal pathways. These attributes enable glycine inputs to summate and effectively control the output gain of SACs, expanding the range over which they compute direction. Serial electron microscopic reconstructions reveal three specific types of ON and OFF narrow-field amacrine cells as the presumptive sources of glycinergic inhibition. Together, these results establish an unexpected role for specific glycinergic amacrine cells in the retinal computation of stimulus direction by SACs.
MeSH term(s)	Amacrine Cells/physiology ; Glycine/metabolism ; Retina/metabolism ; Synapses/metabolism
Chemical Substances	Glycine (TE7660XO1C)
Language	English
Publishing date	2022-02-23
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2649101-1
ISSN	2211-1247 ; 2211-1247
ISSN (online)	2211-1247
ISSN	2211-1247
DOI	10.1016/j.celrep.2022.110410
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Article ; Online: GlyRα2, not GlyRα3, modulates the receptive field surround of OFF retinal ganglion cells.

Zhang, Chi / Nobles, Regina D / McCall, Maureen A

Visual neuroscience

2016 Volume 32, Page(s) E026

Abstract: Receptive fields (RFs) of most retinal ganglion cells (RGCs) consist of an excitatory center and suppressive surround. The RF center arises from the summation of excitatory bipolar cell glutamatergic inputs, whereas the surround arises from lateral ... ...

Abstract	Receptive fields (RFs) of most retinal ganglion cells (RGCs) consist of an excitatory center and suppressive surround. The RF center arises from the summation of excitatory bipolar cell glutamatergic inputs, whereas the surround arises from lateral inhibitory inputs. In the retina, both gamma amino butyric acid (GABA) and glycine are inhibitory neurotransmitters. A clear role for GABAergic inhibition modulating the RGC RF surround has been demonstrated across species. Glycinergic inhibition is more commonly associated with RF center modulation, although there is some evidence that it may contribute to the RF surround. The synaptic glycinergic chloride channels are formed by three homomeric β and two homomeric α subunits that can be glycine receptor (GlyR) α1, α2, α3, or α4. GlyRα composition is responsible for currents with distinct decay kinetics. Their expression within the inner plexiform laminae and neuronal subtypes also differ. We studied the role of GlyR subunit selective modulation of RGC RF surrounds, using mice lacking GlyRα2 (Glra2 -/-), GlyRα3 (Glra3 -/-), or both (Glra2/3 -/-). We chose this molecular genetic approach instead of pharmacological manipulation because there are no subunit selective antagonists and strychnine blocks all GlyRs. Comparisons of annulus-evoked responses among wild type (WT) and GlyRα knockouts (Glra2 -/-, Glra3 -/- and Glra2/3 -/-) show that GlyRα2 inhibition enhances RF surround suppression and post-stimulus excitation in only WT OFF RGCs. Similarities in the responses in Glra2 -/- and Glra2/3 -/- RGCs verify these conclusions. Based on previous and current data, we propose that GlyRα2-mediated input uses a crossover inhibitory circuit. Further, we suggest that GlyRα2 modulates the OFF RGC RF center and surround independently. In summary, our results define a selective GlyR subunit-specific control of RF surround suppression in OFF RGCs.
MeSH term(s)	Animals ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Neural Inhibition/physiology ; Receptors, Glycine/metabolism ; Retinal Ganglion Cells/metabolism
Chemical Substances	Receptors, Glycine ; glycine receptor alpha3 subunit
Language	English
Publishing date	2016-02-16
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	639436-x
ISSN	1469-8714 ; 0952-5238
ISSN (online)	1469-8714
ISSN	0952-5238
DOI	10.1017/S0952523815000280
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Article ; Online: LRIT3 is Required for Nyctalopin Expression and Normal ON and OFF Pathway Signaling in the Retina.

Hasan, Nazarul / Pangeni, Gobinda / Ray, Thomas A / Fransen, Kathryn M / Noel, Jennifer / Borghuis, Bart G / McCall, Maureen A / Gregg, Ronald G

eNeuro

2020 Volume 7, Issue 1

Abstract: The first retinal synapse, photoreceptor→bipolar cell (BC), is both anatomically and functionally complex. Within the same synaptic region, a change in presynaptic glutamate release is sensed by both ON BCs (DBCs) via the metabotropic glutamate receptor ... ...

Abstract	The first retinal synapse, photoreceptor→bipolar cell (BC), is both anatomically and functionally complex. Within the same synaptic region, a change in presynaptic glutamate release is sensed by both ON BCs (DBCs) via the metabotropic glutamate receptor 6 (mGluR6), and OFF BCs (HBCs) via ionotropic glutamate receptors to establish parallel signaling pathways that preferentially encode light increments (ON) or decrements (OFF), respectively. The synaptic structural organization of ON and OFF-type BCs at the photoreceptor terminal differs. DBCs make an invaginating synapse that contains a diverse but incompletely understood complex of interacting proteins (signalplex). HBCs make primarily flat contacts that contain an apparent different set of proteins that is equally uncharacterized. LRIT3 is a synaptic protein known to be essential for ON pathway visual function. In both male and female mice, we demonstrate that LRIT3 interacts with and is required for expression of nyctalopin, and thus TRPM1 at all DBC dendritic tips, but DBC signalplex components are not required for LRIT3 expression. Using whole-cell and multielectrode array (MEA) electrophysiology and glutamate imaging, we demonstrate that the loss of LRIT3 impacts both ON and OFF signaling pathway function. Without LRIT3, excitatory input to type 1 BCs is reduced, as are the visually evoked responses of many OFF retinal ganglion cells (RGCs). We conclude that the absence of LRIT3 expression disrupts excitatory input to OFF BCs and, thus disrupts the normal function of OFF RGCs.
MeSH term(s)	Animals ; Female ; Male ; Membrane Proteins ; Mice ; Mice, Inbred C57BL ; Retina ; Retinal Bipolar Cells ; Signal Transduction ; Synapses
Chemical Substances	Lrit3 protein, mouse ; Membrane Proteins
Language	English
Publishing date	2020-02-11
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2800598-3
ISSN	2373-2822 ; 2373-2822
ISSN (online)	2373-2822
ISSN	2373-2822
DOI	10.1523/ENEURO.0002-20.2020
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Article ; Online: Photobleaching reduction in modulated super-resolution microscopy.

Ghithan, Jafar H / Noel, Jennifer M / Roussel, Thomas J / McCall, Maureen A / Alphenaar, Bruce W / Mendes, Sergio B

Microscopy (Oxford, England)

2020 Volume 70, Issue 3, Page(s) 278–288

Abstract: Important breakthroughs in far-field imaging techniques have been made since the first demonstrations of stimulated emission depletion (STED) microscopy. To date, the most straightforward and widespread deployment of STED microscopy has used continuous ... ...

Abstract	Important breakthroughs in far-field imaging techniques have been made since the first demonstrations of stimulated emission depletion (STED) microscopy. To date, the most straightforward and widespread deployment of STED microscopy has used continuous wave (CW) laser beams for both the excitation and depletion of fluorescence emission. A major drawback of the CW STED imaging technique has been photobleaching effects due to the high optical power needed in the depletion beam to reach sub-diffraction resolution. To overcome this hurdle, we have applied a synchronous detection approach based on modulating the excitation laser beam, while keeping the depletion beam at CW operation, and frequency filtering the collected signal with a lock-in amplifier to record solely the super-resolved fluorescence emission. We demonstrate here that such approach allows an important reduction in the optical power of both laser beams that leads to measurable decreases in photobleaching effects in STED microscopy. We report super-resolution images with relatively low powers for both the excitation and depletion beams. In addition, typical unwanted scattering effects and background signal generated from the depletion beam, which invariably arises from mismatches in refractive index in the material composing the sample, are largely reduced by using the modulated STED approach. The capability of acquiring super-resolution images with relatively low power is quite relevant for studying a variety of samples, but particularly important for biological species as exemplified in this work.
MeSH term(s)	Animals ; Fluorescence ; Image Processing, Computer-Assisted/methods ; Lasers ; Mice ; Mice, Transgenic ; Microscopy, Fluorescence/methods ; Optical Imaging/methods ; Photobleaching
Language	English
Publishing date	2020-10-16
Publishing country	England
Document type	Journal Article
ZDB-ID	2707496-1
ISSN	2050-5701 ; 2050-5698
ISSN (online)	2050-5701
ISSN	2050-5698
DOI	10.1093/jmicro/dfaa062
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Article ; Online: Electroretinogram of the Cone-Dominant Thirteen-Lined Ground Squirrel during Euthermia and Hibernation in Comparison with the Rod-Dominant Brown Norway Rat.

Zhang, Hanmeng / Sajdak, Benjamin S / Merriman, Dana K / McCall, Maureen A / Carroll, Joseph / Lipinski, Daniel M

Investigative ophthalmology & visual science

2020 Volume 61, Issue 6, Page(s) 6

Abstract: Purpose: The majority of small animal species used in research are nocturnal, with retinae that are anatomically and functionally dissimilar from humans, complicating their use as disease models. Herein we characterize the retinal structure and ... ...

Abstract	Purpose: The majority of small animal species used in research are nocturnal, with retinae that are anatomically and functionally dissimilar from humans, complicating their use as disease models. Herein we characterize the retinal structure and electrophysiological function of the diurnal, cone-dominant 13-lined ground squirrel (13-LGS) retina during euthermia and in hibernation. Methods: Full-field electroretinography (ERG) was performed in 13-LGS and Brown Norway (BN) rat models to establish baseline values for retinal function in each species, including following intravitreal injection of pharmacologic agents to selectively block the contributions of ON- and OFF-bipolar cells. The effect of hibernation-associated retinal remodeling on electrophysiological function was assessed in 13-LGS during torpor and emergence, with correlative histology performed using transmission electron microscopy. Results: Under light-adapted conditions, the a-, b-, and d-wave amplitude of the 13-LGS was significantly greater than that of the BN rat. Retinal function was absent in the 13-LGS during hibernation and correlated to widespread disruption of photoreceptor and RPE structure. Remarkably, both retinal function and structure recovered rapidly on emergence from hibernation, with ERG responses reaching normal amplitude within 6 hours. Conclusions: ERG responses for both BN rats and 13-LGS reflect the relative proportions of cone photoreceptors present within the retinae, indicating that the cone-dominant 13-LGS may be a potentially useful model for studying human central retinal function and disease. That retinal remodeling and restoration of electrophysiological function occurs rapidly on emergence from hibernation implies the 13-LGS may also be a useful tool for studying aspects of retinal physiology and recovery from injury.
MeSH term(s)	Animals ; Electroretinography ; Excitatory Amino Acid Agonists/pharmacology ; Female ; Hibernation/physiology ; Intravitreal Injections ; Male ; Rats ; Rats, Inbred BN ; Receptors, Kainic Acid/metabolism ; Receptors, Metabotropic Glutamate/metabolism ; Retina/physiology ; Retina/ultrastructure ; Retinal Bipolar Cells/drug effects ; Retinal Cone Photoreceptor Cells/physiology ; Retinal Cone Photoreceptor Cells/ultrastructure ; Retinal Rod Photoreceptor Cells/physiology ; Retinal Rod Photoreceptor Cells/ultrastructure ; Sciuridae ; Torpor/physiology
Chemical Substances	Excitatory Amino Acid Agonists ; Receptors, Kainic Acid ; Receptors, Metabotropic Glutamate
Language	English
Publishing date	2020-09-01
Publishing country	United States
Document type	Comparative Study ; Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	391794-0
ISSN	1552-5783 ; 0146-0404
ISSN (online)	1552-5783
ISSN	0146-0404
DOI	10.1167/iovs.61.6.6
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Article ; Online: Nuclear Factor I in neurons, glia and during the formation of Müller glia-derived progenitor cells in avian, porcine and primate retinas.

El-Hodiri, Heithem M / Campbell, Warren A / Kelly, Lisa E / Hawthorn, Evan C / Schwartz, Maura / Jalligampala, Archana / McCall, Maureen A / Meyer, Kathrin / Fischer, Andy J

The Journal of comparative neurology

2021 Volume 530, Issue 8, Page(s) 1213–1230

Abstract: The regenerative potential of Müller glia (MG) is extraordinary in fish, poor in chick and terrible in mammals. In the chick model, MG readily reprogram into proliferating Müller glia-derived progenitor cells (MGPCs), but neuronal differentiation is very ...

Abstract	The regenerative potential of Müller glia (MG) is extraordinary in fish, poor in chick and terrible in mammals. In the chick model, MG readily reprogram into proliferating Müller glia-derived progenitor cells (MGPCs), but neuronal differentiation is very limited. The factors that suppress the neurogenic potential of MGPCs in the chick are slowly being revealed. Isoforms of Nuclear Factor I (NFI) are cell-intrinsic factors that limit neurogenic potential; these factors are required for the formation of MG in the developing mouse retina and deletion of these factors reprograms MG into neuron-like cells in mature mouse retina. Accordingly, we sought to characterize the patterns of expression of NFIs in the developing, mature and damaged chick retina. In addition, we characterized patterns of expression of NFIs in the retinas of large mammals, pigs and monkeys. Using a combination of single-cell RNA-sequencing (scRNA-seq) and immunolabeling, we probed for patterns of expression. In embryonic chick, levels of NFIs are very low in early E5 (embryonic day 5) retinal progenitor cells (RPCs), upregulated in E8 RPCs, further upregulated in differentiating MG at E12 and E15. NFIs are maintained in mature resting MG, microglia and neurons. Levels of NFIs are reduced in activated MG in retinas treated with NMDA and/or insulin+FGF2, and further downregulated in proliferating MGPCs. However, levels of NFIs in MGPCs were significantly higher than those seen in RPCs. Immunolabeling for NFIA and NFIB closely matched patterns of expression revealed in different types of retinal neurons and glia, consistent with findings from scRNA-seq. In addition, we find expression of NFIA and NFIB through progenitors in the circumferential marginal zone at the far periphery of the retina. We find similar patterns of expression for NFIs in scRNA-seq databases for pig and monkey retinas. Patterns of expression of NFIA and NFIB were validated with immunofluorescence in pig and monkey retinas wherein these factors were predominantly detected in MG and a few types of inner retinal neurons. In summary, NFIA and NFIB are prominently expressed in developing chick retina and by mature neurons and glia in the retinas of chicks, pigs and monkeys. Although levels of NFIs are decreased in chick, in MGPCs these levels remain higher than those seen in neurogenic RPCs. We propose that the neurogenic potential of MGPCs in the chick retina is suppressed by NFIs.
MeSH term(s)	Animals ; Cell Proliferation/physiology ; Mammals ; Mice ; NFI Transcription Factors/metabolism ; Neuroglia/metabolism ; Neurons/metabolism ; Primates/metabolism ; Retina ; Signal Transduction/physiology ; Stem Cells ; Swine
Chemical Substances	NFI Transcription Factors
Language	English
Publishing date	2021-12-15
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	3086-7
ISSN	1096-9861 ; 0021-9967 ; 0092-7317
ISSN (online)	1096-9861
ISSN	0021-9967 ; 0092-7317
DOI	10.1002/cne.25270
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Article: Prenatal Exposure to Curcumin Protects Rod Photoreceptors in a Transgenic Pro23His Swine Model of Retinitis Pigmentosa.

Scott, Patrick A / Kaplan, Henry J / McCall, Maureen A

Translational vision science & technology

2015 Volume 4, Issue 5, Page(s) 5

Abstract: Purpose: Rhodopsin localization and rod photoreceptor (PR) morphology is altered in embryonic transgenic (Tg) Pro23His (P23H) miniswine. At birth, the Tg P23H swine retina lacks rod driven signaling. Curcumin, a neuroprotective food additive, has been ... ...

Abstract	Purpose: Rhodopsin localization and rod photoreceptor (PR) morphology is altered in embryonic transgenic (Tg) Pro23His (P23H) miniswine. At birth, the Tg P23H swine retina lacks rod driven signaling. Curcumin, a neuroprotective food additive, has been shown to rescue Tg P23H rat rod PRs and promote normal trafficking of rhodopsin. We tested the hypothesis that prenatal exposure to curcumin would prevent PR morphological changes in Tg P23H miniswine retinae. Methods: A domestic sow was inseminated with semen from a Tg P23H miniswine founder. Her daily diet was supplemented with curcumin (100 mg/Kg body weight) from embryonic (E) day 80 to E112. The same diet without curcumin was fed to a second inseminated control sow. At E112, 2 days before parturition, both sows were euthanized. Their embryos were harvested, genotyped, and their eyes enucleated and prepared for morphological evaluation. Results: In all pigs, we measured mean outer retinal thickness, localization of rhodopsin, and rod PR morphology. Curcumin-treated Tg P23H swine embryonic retinas were similar to WT. Untreated Tg P23H embryonic retinas show significant degenerative effects; their outer retina was thinner, rod PR morphology was abnormal, and rhodopsin was mislocalized to the outer nuclear layer (ONL). Conclusions: These data support a role for curcumin as a neuroprotective agent that prevents/delays morphological abnormalities associated with rod PR degeneration in this Tg P23H swine model of retinitis pigmentosa (RP). Translational relevance: Curcumin, a Food and Drug Administration-approved dietary supplement, may arrest/delay PR degeneration if ingested by individuals at risk for developing RP.
Language	English
Publishing date	2015-09-16
Publishing country	United States
Document type	Journal Article
ZDB-ID	2674602-5
ISSN	2164-2591
ISSN	2164-2591
DOI	10.1167/tvst.4.5.5
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Article ; Online: Intermolecular Interaction between Anchoring Subunits Specify Subcellular Targeting and Function of RGS Proteins in Retina ON-Bipolar Neurons.

Sarria, Ignacio / Orlandi, Cesare / McCall, Maureen A / Gregg, Ronald G / Martemyanov, Kirill A

The Journal of neuroscience : the official journal of the Society for Neuroscience

2016 Volume 36, Issue 10, Page(s) 2915–2925

Abstract: In vertebrate retina, light responses generated by the rod photoreceptors are transmitted to the second-order neurons, the ON-bipolar cells (ON-BC), and this communication is indispensible for vision in dim light. In ON-BCs, synaptic transmission is ... ...

Abstract	In vertebrate retina, light responses generated by the rod photoreceptors are transmitted to the second-order neurons, the ON-bipolar cells (ON-BC), and this communication is indispensible for vision in dim light. In ON-BCs, synaptic transmission is initiated by the metabotropic glutamate receptor, mGluR6, that signals via the G-protein Go to control opening of the effector ion channel, TRPM1. A key role in this process belongs to the GTPase Activating Protein (GAP) complex that catalyzes Go inactivation upon light-induced suppression of glutamate release in rod photoreceptors, thereby driving ON-BC depolarization to changes in synaptic input. The GAP complex has a striking molecular complexity. It contains two Regulator of G-protein Signaling (RGS) proteins RGS7 and RGS11 that directly act on Go and two adaptor subunits: RGS Anchor Protein (R9AP) and the orphan receptor, GPR179. Here we examined the organizational principles of the GAP complex in ON-BCs. Biochemical experiments revealed that RGS7 binds to a conserved site in GPR179 and that RGS11 in vivo forms a complex only with R9AP. R9AP and GPR179 are further integrated via direct protein-protein interactions involving their cytoplasmic domains. Elimination of GPR179 prevents postsynaptic accumulation of R9AP. Furthermore, concurrent knock-out of both R9AP and RGS7 does not reconfigure the GAP complex and completely abolishes synaptic transmission, resulting in a novel mouse model of night blindness. Based on these results, we propose a model of hierarchical assembly and function of the GAP complex that supports ON-BCs visual signaling.
MeSH term(s)	Animals ; Cadmium Chloride/pharmacology ; DNA-Binding Proteins/metabolism ; Female ; Gene Expression Regulation/genetics ; Gene Expression Regulation/physiology ; HEK293 Cells ; Humans ; Light ; Macromolecular Substances/metabolism ; Male ; Membrane Proteins/deficiency ; Membrane Proteins/genetics ; Mice ; Mice, Transgenic ; Models, Molecular ; Phosphoproteins/metabolism ; RGS Proteins/genetics ; RGS Proteins/metabolism ; Receptors, G-Protein-Coupled/genetics ; Receptors, G-Protein-Coupled/metabolism ; Receptors, Metabotropic Glutamate/metabolism ; Retina/cytology ; Retinal Bipolar Cells/physiology ; Synaptic Transmission/physiology
Chemical Substances	DNA-Binding Proteins ; GPR17 protein, human ; Macromolecular Substances ; Membrane Proteins ; Phosphoproteins ; R9AP protein, mouse ; RGS Proteins ; Receptors, G-Protein-Coupled ; Receptors, Metabotropic Glutamate ; Rgs7 protein, mouse ; metabotropic glutamate receptor 6 ; Ctbp2 protein, mouse (EC 1.1.-) ; Cadmium Chloride (J6K4F9V3BA)
Language	English
Publishing date	2016-03-10
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	604637-x
ISSN	1529-2401 ; 0270-6474
ISSN (online)	1529-2401
ISSN	0270-6474
DOI	10.1523/JNEUROSCI.3833-15.2016
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