VDAC in Retinal Health and Disease.

The retina, a tissue of the central nervous system, is vital for vision as its photoreceptors capture light and transform it into electrical signals, which are further processed before they are sent to the brain to be interpreted as images. The retina is unique in that it is continuously exposed to light and has the highest metabolic rate and demand for energy amongst all the tissues in the body. Consequently, the retina is very susceptible to oxidative stress.

Targeting the overexpressed mitochondrial protein VDAC1 in a mouse model of Alzheimer's disease protects against mitochondrial dysfunction and mitigates brain pathology.

Background: Alzheimer's disease (AD) exhibits mitochondrial dysfunctions associated with dysregulated metabolism, brain inflammation, synaptic loss, and neuronal cell death. As a key protein serving as the mitochondrial gatekeeper, the voltage-dependent anion channel-1 (VDAC1) that controls metabolism and Ca homeostasis is positioned at a convergence point for various cell survival and death signals. Here, we targeted VDAC1 with VBIT-4, a newly developed inhibitor of VDAC1 that prevents its pro-apoptotic activity, and mitochondria dysfunction.

Wolfberry-derived zeaxanthin dipalmitate delays retinal degeneration in a mouse model of retinitis pigmentosa through modulating STAT3, CCL2 and MAPK pathways.

Retinitis pigmentosa (RP) is a group of inherited photoreceptor degeneration diseases that causes blindness without effective treatment. The pathogenesis of retinal degeneration involves mainly oxidative stress and inflammatory responses. Zeaxanthin dipalmitate (ZD), a wolfberry-derived carotenoid, has anti-inflammatory and anti-oxidative stress effects.

Arginyltransferase (Ate1) regulates the RGS7 protein level and the sensitivity of light-evoked ON-bipolar responses.

Regulator of G-protein signaling 7 (RGS7) is predominately present in the nervous system and is essential for neuronal signaling involving G-proteins. Prior studies in cultured cells showed that RGS7 is regulated via proteasomal degradation, however no protein is known to facilitate proteasomal degradation of RGS7 and it has not been shown whether this regulation affects G-protein signaling in neurons. Here we used a knockout mouse model with conditional deletion of arginyltransferase (Ate1) in the nervous system and found that in retinal ON bipolar cells, where RGS7 modulates a G-protein to signal light increments, deletion of Ate1 raised the level of RGS7.

Inhibition of non-NMDA ionotropic glutamate receptors delays the retinal degeneration in rd10 mouse.

Retinitis pigmentosa (RP) is a hereditary blinding disease characterized by neurodegeneration of photoreceptors. Retinal ganglion cells (RGCs) in animal models of RP exhibit an abnormally high spontaneous activity that interferes with signal processing. Blocking AMPA/Kainate receptors by bath application of CNQX decreases the spontaneous firing, suggesting that inhibiting these receptors in vivo may help maintain the function of inner retinal neurons in rd10 mice experiencing photoreceptor degeneration.

Lycium Barbarum Polysaccharides Protect Retina in rd1 Mice During Photoreceptor Degeneration.

Purpose: As an active component in wolfberry, lycium barbarum polysaccharides (LBP) are capable of protecting retinal neurons in several animal disease models. Here, we asked whether LBP rescues the retinal morphology and function in rd1 mouse, a photoreceptor fast-degenerating animal model of retinitis pigmentosa, and in particular focused on LBP's effects on the function of retinal ganglion cells (RGCs) during photoreceptor degeneration.

Methods: An equal volume of LBP or control vehicle was daily intraperitoneal (i.

Frizzled3 Shapes the Development of Retinal Rod Bipolar Cells.

Purpose: Frizzled3 (Fzd3), a member of the core planar cell polarity (PCP) family in mammals, contributes to visual development by guiding axonal projections of some retinal ganglion cells. However, its other functions in the maturation of the visual system, especially the retina, remain elusive. The present study explores the role of Fzd3 in retinal development by focusing on rod bipolar cells (RBCs).

Lack of mGluR6-related cascade elements leads to retrograde trans-synaptic effects on rod photoreceptor synapses via matrix-associated proteins.

Heterotrimeric G-proteins couple metabotropic receptors to downstream effectors. In retinal ON bipolar cells, Go couples the metabotropic receptor mGluR6 to the TRPM1 channel and closes it in the dark, thus hyperpolarizing the cell. Light, via GTPase-activating proteins, deactivates Go , opens TRPM1 and depolarizes the cell.

The TRPM1 channel in ON-bipolar cells is gated by both the α and the βγ subunits of the G-protein Go.

Transmission from photoreceptors to ON bipolar cells in mammalian retina is mediated by a sign-inverting cascade. Upon binding glutamate, the metabotropic glutamate receptor mGluR6 activates the heterotrimeric G-protein Gαoβ3γ13, and this leads to closure of the TRPM1 channel (melastatin). TRPM1 is thought to be constitutively open, but the mechanism that leads to its closure is unclear.

Differential function of Gγ13 in rod bipolar and ON cone bipolar cells.

Heterotrimeric G-proteins (comprising Gα and Gβγ subunits) are critical for coupling of metabotropic receptors to their downstream effectors. In the retina, glutamate released from photoreceptors in the dark activates metabotropic glutamate receptor 6 (mGluR6) receptors in ON bipolar cells; this leads to activation of Go , closure of transient receptor potential melastatin 1 channels and hyperpolarization of these cells. Go comprises Gαo , Gβ3 and a Gγ.

PDE9A is expressed in the inner retina and contributes to the normal shape of the photopic ERG waveform.

The ubiquitous second messenger cGMP is synthesized by guanylyl cyclase and hydrolyzed by phosphodiesterase (PDE). cGMP mediates numerous signaling pathways in multiple tissues. In the retina, cGMP regulates signaling in nearly every cell class including photoreceptors, bipolar cells, amacrine cells, and ganglion cells.

Localization of Cacna1s to ON bipolar dendritic tips requires mGluR6-related cascade elements.

Purpose: L-type voltage gated calcium channels in retina localize primarily at the presynaptic active zones of photoreceptors and bipolar cells where they modulate glutamate release. However, the pore forming subunit Cacna1s of certain L-type channels is also expressed postsynaptically at the tips of ON bipolar cell dendrites where it colocalizes with mGluR6, but has an unknown function. At these dendritic tips, the components of the mGluR6 signaling cascade cluster together in a macromolecular complex, and each one's localization often depends on that of the others.

"mGlu Receptors in the Retina" - WIREs Membrane Transport and Signaling.

Glutamate, a key neurotransmitter in the vertebrate retina, acts via ionotropic and metabotropic receptors. Retina expresses mRNA for all metabotropic glutamate receptors and proteins for all but mGluR3. Every retinal cell class expresses one or more of these receptors.

Cones respond to light in the absence of transducin β subunit.

Mammalian cones respond to light by closing a cGMP-gated channel via a cascade that includes a heterotrimeric G-protein, cone transducin, comprising Gαt2, Gβ3 and Gγt2 subunits. The function of Gβγ in this cascade has not been examined. Here, we investigate the role of Gβ3 by assessing cone structure and function in Gβ3-null mouse (Gnb3(-/-)).

Metabotropic glutamate receptor 6 signaling enhances TRPM1 calcium channel function and increases melanin content in human melanocytes.

Mutations in TRPM1, a calcium channel expressed in retinal bipolar cells and epidermal melanocytes, cause complete congenital stationary night blindness with no discernible skin phenotype. In the retina, TRPM1 activity is negatively coupled to metabotropic glutamate receptor 6 (mGluR6) signaling through Gαo and TRPM1 mutations result in the loss of responsiveness of TRPM1 to mGluR6 signaling. Here, we show that human melanocytes express mGluR6, and treatment of melanocytes with L-AP4, a type III mGluR-selective agonist, enhances Ca(2+) uptake.

Kir2.4 surface expression and basal current are affected by heterotrimeric G-proteins.

Kir2.4, a strongly rectifying potassium channel that is localized to neurons and is especially abundant in retina, was fished with yeast two-hybrid screen using a constitutively active Gαo1. Here, we wished to determine whether and how Gαo affects this channel.

Gβ3 is required for normal light ON responses and synaptic maintenance.

Heterotrimeric G-proteins, comprising Gα and Gβγ subunits, couple metabotropic receptors to various downstream effectors and contribute to assembling and trafficking receptor-based signaling complexes. A G-protein β subunit, Gβ(3), plays a critical role in several physiological processes, as a polymorphism in its gene is associated with a risk factor for several disorders. Retinal ON bipolar cells express Gβ(3), and they provide an excellent system to study its role.

mGluR6 deletion renders the TRPM1 channel in retina inactive.

In darkness, glutamate released from photoreceptors activates the metabotropic glutamate receptor 6 (mGluR6) on retinal ON bipolar cells. This activates the G protein G(o), which then closes transient receptor potential melastatin 1 (TRPM1) channels, leading to cells' hyperpolarization. It has been generally assumed that deleting mGluR6 would render the cascade inactive and the ON bipolar cells constitutively depolarized.

mGluR6 transcripts in non-neuronal tissues.

To study mGluR6 expression, the authors investigated two transgenic mouse lines that express enhanced green fluorescent protein (GFP) under control of mGluR6 promoter. In retina, GFP was expressed exclusively in all ON bipolar cell types, either uniformly across all cells of this class (line 5) or in a mosaic (patchy) fashion (line 1). In brain, GFP was found in certain cortical areas, superior colliculus, axons of the corpus callosum, accessory olfactory bulb, and cells of the subcommissural organ.

Imaging light responses of targeted neuron populations in the rodent retina.

Decoding the wiring diagram of the retina requires simultaneous observation of activity in identified neuron populations. Available recording methods are limited in their scope: electrodes can access only a small fraction of neurons at once, whereas synthetic fluorescent indicator dyes label tissue indiscriminately. Here, we describe a method for studying retinal circuitry at cellular and subcellular levels combining two-photon microscopy and a genetically encoded calcium indicator.

Autoantibodies in melanoma-associated retinopathy target TRPM1 cation channels of retinal ON bipolar cells.

Melanoma-associated retinopathy (MAR) is characterized by night blindness, photopsias, and a selective reduction of the electroretinogram b-wave. In certain cases, the serum contains autoantibodies that react with ON bipolar cells, but the target of these autoantibodies has not been identified. Here we show that the primary target of autoantibodies produced in MAR patients with reduced b-wave is the TRPM1 cation channel, the newly identified transduction channel in ON bipolar cells.

Immunocytochemical evidence that monkey rod bipolar cells use GABA.

Certain bipolar cells in most species immunostain for GABA or its synthesizing enzyme glutamic acid decarboxylase. However, it is unknown whether they actually release GABA and, if so, from which cellular compartment and by what release mechanism. We investigated these questions in monkey retina where rod bipolar cells immunostain for GABA.

Ret-PCP2 colocalizes with protein kinase C in a subset of primate ON cone bipolar cells.

Purkinje cell protein 2 (PCP2), a member of the family of guanine dissociation inhibitors and a strong interactor with the G-protein subunit G alpha(o), localizes to retinal ON bipolar cells. The retina-specific splice variant of PCP2, Ret-PCP2, accelerates the light response of rod bipolar cells by modulating the mGluR6 transduction cascade. All ON cone bipolar cells express mGluR6 and G alpha(o), but only a subset expresses Ret-PCP2.

Retinal ON bipolar cells express a new PCP2 splice variant that accelerates the light response.

PCP2, a member of the GoLoco domain-containing family, is present exclusively in cerebellar Purkinje cells and retinal ON bipolar cells. Its function in these tissues is unknown. Biochemical and expression system studies suggest that PCP2 is a guanine nucleotide dissociation inhibitor, although a guanine nucleotide exchange factor has also been suggested.