Congenital stationary night blindness (CSNB) is a group of non-progressive retinal diseases characterized by impaired scotopic vision. Mutations in a number of genes have been shown to be associated with CSNB. They generally affect synaptic transmission between photoreceptors and the second order bipolar cells. When the mutant gene is expressed only in rods, or rod bipolar cells, the phenotype is limited to night blindness. However, when the mutant gene function is also required for synaptic transmission between cones and cone bipolar cells, further visual symptoms are apparent such as myopia, hyperopia, nystagmus, and reduced visual acuity. One such example are mutations in GRM6, the gene encoding mGluR6, which cause an autosomal recessive form of CSNB. In the retina, visual information is segregated into pathways that respond to increases and decreases in light intensity. At the first retinal synapse, the tonic release of glutamate from photoreceptor terminals maintains a high synaptic concentration in darkness that decreases in response to light. Two types of postsynaptic cells, the ON- and OFF-bipolar cells, respond with opposite polarity to glutamate released by photoreceptors, thus establishing the opposing visual pathways. The basis of signaling in OFF-bipolar cells, which relies on the activation of ionotropic glutamate receptors, is well understood. The signaling pathway that generates the light response in ON-bipolar cells, however, is more complex, and the molecular mechanisms remain to be elucidated. The ON-bipolar cell signaling pathway originates with a unique metabotropic glutamate receptor, mGluR6, which is found on the dendrites of ON-bipolar cells. mGluR6 acts via a G-protein, GO, to regulate the activity of an unidentified cation channel such that the light-induced decrease in synaptic glutamate opens the channel and depolarizes the cell. Recently, it has been reported that CSNB in Appaloosa horses is associated with a mutation causing a reduced expression of the TRPM1 cation channel. We hypothesize that TRPM1, and possibly other related TRP channels, are the cation channels coupled to mGluR6 that mediate the depolarizing light response of ON- bipolar cells. We further suggest that mutations in TRP channels will cause CSNB. Using a combination of biochemical, immunohistochemical, and electrophysiological approaches, we will test this hypothesis by answering the following questions: 1. Which TRP channel variants are expressed in ON-bipolar cells? 2. Do mice that carry null mutations in TRP channels expressed in bipolar cells have CSNB? 3. Can the physiological and pharmacological properties of retinal ON bipolar cell responses be reproduced in transfected HEK cells expressing the proper combination of TRP channel variants? The data from this study will contribute to the elucidation of the signaling pathway in the ON-bipolar cell, a fundamental, yet poorly understood, step in visual processing.
Congenital stationary night blindness (CSNB) is an inherited eye disorder causing night blindness, and also often shortsightedness, nystagmus (involuntary eye movement), and reduced visual acuity, even under normal lighting conditions. The proposed research will determine if abnormal ion channel function in the eye can be a cause of CSNB.
|NeuillÃ©, Marion; Morgans, Catherine W; Cao, Yan et al. (2015) LRIT3 is essential to localize TRPM1 to the dendritic tips of depolarizing bipolar cells and may play a role in cone synapse formation. Eur J Neurosci 42:1966-75|
|Brown, R Lane; Xiong, Wei-Hong; Peters, James H et al. (2015) TRPM3 expression in mouse retina. PLoS One 10:e0117615|
|Xiong, Wei-Hong; Brown, R Lane; Reed, Brian et al. (2015) Voriconazole, an antifungal triazol that causes visual side effects, is an inhibitor of TRPM1 and TRPM3 channels. Invest Ophthalmol Vis Sci 56:1367-73|
|Meighan, Starla E; Meighan, Peter C; Rich, Elizabeth D et al. (2013) Cyclic nucleotide-gated channel subunit glycosylation regulates matrix metalloproteinase-dependent changes in channel gating. Biochemistry 52:8352-62|
|Meighan, Peter C; Meighan, Starla E; Rich, Elizabeth D et al. (2012) Matrix metalloproteinase-9 and -2 enhance the ligand sensitivity of photoreceptor cyclic nucleotide-gated channels. Channels (Austin) 6:181-96|
|Duricka, Deborah L; Brown, R Lane; Varnum, Michael D (2012) Defective trafficking of cone photoreceptor CNG channels induces the unfolded protein response and ER-stress-associated cell death. Biochem J 441:685-96|