Abstract
Normal vision depends on signaling from photoreceptors to central visual areas via parallel pathways that are optimized for detecting increments (ON) or decrements (OFF) in light intensity. The divergence of these two pathways occurs at the first synapse. The OFF pathway is mediated via Off-bipolar cells that hyperpolarize in response to light increments because they utilize ionotropic glutamate receptors. On-bipolar cells that initiate the ON pathway utilize metabotropic glutamate receptors to signal via a G-protein cascade to the transient receptor potential melastatin 1 (TRPM1) channel, and depolarize in response to light increments. Several proteins (mGluR6, TRPM1, GPR179, RGS7, RGS11, nyctalopin, LRIT3, Gα0, Gβ3, Gβ5, and R9AP) have been shown to be required for normal functioning of the depolarizing bipolar cell cascade. Here, we use immunohistochemistry in mouse models that lack one or more of these proteins to understand their interdependency. The picture that evolves is that of a large complex, in which the removal of any one element results in either delocalization of or decreased expression of other elements.
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References
Audo I, Kohl S, Leroy BP, Munier FL, Guillonneau X et al (2009) TRPM1 is mutated in patients with autosomal-recessive complete congenital stationary night blindness. Am J Hum Genet 85:720–729
Audo I, Bujakowska K, Orhan E, Poloschek CM, Defoort-Dhellemmes S et al (2012) Whole-exome sequencing identifies mutations in gpr179 leading to autosomal-recessive complete congenital stationary night blindness. Am J Hum Genet 90:321–330
Bech-Hansen NT, Naylor MJ, Maybaum TA, Sparkes RL, Koop B et al (2000) Mutations in NYX, encoding the leucine-rich proteoglycan nyctalopin, cause X-linked complete congenital stationary night blindness. Nat Genet 26:319–323
Bellone RR, Brooks SA, Sandmeyer L, Murphy BA, Forsyth G et al (2008) Differential gene expression of TRPM1, the potential cause of congenital stationary night blindness and coat spotting patterns (LP) in the Appaloosa horse (Equus caballus). Genetics 179:1861–1870
Bellone RR, Forsyth G, Leeb T, Archer S, Sigurdsson S et al (2010) Fine-mapping and mutation analysis of TRPM1: a candidate gene for leopard complex (LP) spotting and congenital stationary night blindness in horses. Brief Funct Genomics 9:193–207
Bijveld MM, Florijn RJ, Bergen AA, van den Born LI, Kamermans M et al (2013) Genotype and phenotype of 101 Dutch patients with congenital stationary night blindness. Ophthalmology 120:2072–2081
Cao Y, Song H, Okawa H, Sampath AP, Sokolov M, Martemyanov KA (2008) Targeting of RGS7/Gbeta5 to the dendritic tips of ON-bipolar cells is independent of its association with membrane anchor R7BP. J Neurosci 28:10443–10449
Cao Y, Masuho I, Okawa H, Xie K, Asami J et al (2009) Retina-specific GTPase accelerator RGS11/G beta 5S/R9AP is a constitutive heterotrimer selectively targeted to mGluR6 in ON-bipolar neurons. J Neurosci 29:9301–9313
Cao Y, Posokhova E, Martemyanov KA (2011) TRPM1 forms complexes with nyctalopin in vivo and accumulates in postsynaptic compartment of ON-bipolar neurons in mGluR6-dependent manner. J Neurosci 31:11521–11526
Cao Y, Pahlberg J, Sarria I, Kamasawa N, Sampath AP, Martemyanov KA (2012) Regulators of G protein signaling RGS7 and RGS11 determine the onset of the light response in ON bipolar neurons. Proc Natl Acad Sci U S A 109:7905–7910
Devi S, Markandeya Y, Maddodi N, Dhingra A, Vardi N et al (2013) Metabotropic glutamate receptor 6 signaling enhances TRPM1 calcium channel function and increases melanin content in human melanocytes. Pigment Cell Melanoma Res 26:348–356
Dhingra A, Lyubarsky A, Jiang M, Pugh EN Jr, Birnbaumer L et al (2000) The light response of ON bipolar neurons requires G[alpha]o. J Neurosci 20:9053–9058
Dhingra A, Jiang M, Wang TL, Lyubarsky A, Savchenko A et al (2002) Light response of retinal ON bipolar cells requires a specific splice variant of Galpha(o). J Neurosci 22:4878–4884
Dhingra A, Ramakrishnan H, Neinstein A, Fina ME, Xu Y et al (2012) Gbeta3 is required for normal light ON responses and synaptic maintenance. J Neurosci 32:11343–11355
Dryja TP, McGee TL, Berson EL, Fishman GA, Sandberg MA et al (2005) Night blindness and abnormal cone electroretinogram ON responses in patients with mutations in the GRM6 gene encoding mGluR6. Proc Natl Acad Sci U S A 102:4884–4889
Gregg RG, Mukhopadhyay S, Candille SI, Ball SL, Pardue MT et al (2003) Identification of the gene and the mutation responsible for the mouse nob phenotype. Invest Ophthalmol Vis Sci 44:378–384
Gregg RG, Kamermans M, Klooster J, Lukasiewicz PD, Peachey NS et al (2007) Nyctalopin expression in retinal bipolar cells restores visual function in a mouse model of complete X-linked congenital stationary night blindness. J Neurophysiol 98:3023–3033
Jacobi FK, Andreasson S, Langrova H, Meindl A, Zrenner E et al (2002) Phenotypic expression of the complete type of X-linked congenital stationary night blindness in patients with different mutations in the NYX gene. Graefes Arch Clin Exp Ophthalmol 240:822–828
Koike C, Obara T, Uriu Y, Numata T, Sanuki R et al (2010) TRPM1 is a component of the retinal ON bipolar cell transduction channel in the mGluR6 cascade. Proc Natl Acad Sci U S A 107:332–337
Leroy BP, Budde BS, Wittmer M, De Baere E, Berger W, Zeitz C (2009) A common NYX mutation in Flemish patients with X linked CSNB. Br J Ophthalmol 93:692–696
Li Z, Sergouniotis PI, Michaelides M, Mackay DS, Wright GA et al (2009) Recessive mutations of the gene TRPM1 abrogate ON bipolar cell function and cause complete congenital stationary night blindness in humans. Am J Hum Genet 85:711–719
Maddox DM, Vessey KA, Yarbrough GL, Invergo BM, Cantrell DR et al (2008) Allelic variance between GRM6 mutants, Grm6nob3 and Grm6nob4 results in differences in retinal ganglion cell visual responses. J Physiol 586:4409–4424
Masu M, Iwakabe H, Tagawa Y, Miyoshi T, Yamashita M et al (1995) Specific deficit of the ON response in visual transmission by targeted disruption of the mGluR6 gene. Cell 80:757–765
Morgans CW, Weiwei L, Wensel TG, Brown RL, Perez-Leon JA et al (2007) Gbeta5-RGS complexes co-localize with mGluR6 in retinal ON-bipolar cells. Eur J Neurosci 26:2899–2905
Morgans CW, Zhang J, Jeffrey BG, Nelson SM, Burke NS et al (2009) TRPM1 is required for the depolarizing light response in retinal ON-bipolar cells. Proc Natl Acad Sci U S A 106:19174–19178
Neuille M, El Shamieh S, Orhan E, Michiels C, Antonio A et al (2014) Lrit3 Deficient Mouse (nob6): a novel model of complete congenital stationary night blindness (cCSNB). PLoS ONE 9:e90342
O’Connor E, Allen LE, Bradshaw K, Boylan J, Moore AT, Trump D (2006) Congenital stationary night blindness associated with mutations in GRM6 encoding glutamate receptor MGluR6. Br J Ophthalmol 90:653–654
Orlandi C, Posokhova E, Masuho I, Ray TA, Hasan N et al (2012) GPR158/179 regulate G protein signaling by controlling localization and activity of the RGS7 complexes. J Cell Biol 197:711–719
Orlandi C, Cao Y, Martemyanov KA (2013) Orphan receptor GPR179 forms macromolecular complexes with components of metabotropic signaling cascade in retina ON-bipolar neurons. Invest Ophthalmol Vis Sci 54:7153–7161
Pardue MT, McCall MA, LaVail MM, Gregg RG, Peachey NS (1998) A naturally occurring mouse model of X-linked congenital stationary night blindness. Invest Ophthalmol Vis Sci 39:2443–2449
Peachey NS, Pearring JN, Bojang P Jr, Hirschtritt ME, Sturgill-Short G et al (2012a) Depolarizing bipolar cell dysfunction due to a Trpm1 point mutation. J Neurophysiol 108:2442–2451
Peachey NS, Ray TA, Florijn R, Rowe LB, Sjoerdsma T et al (2012b) GPR179 is required for depolarizing bipolar cell function and is mutated in autosomal-recessive complete congenital stationary night blindness. Am J Hum Genet 90:331–339
Pearring JN, Bojang P, Shen Y, Koike C, Furukawa T et al (2011) A role for nyctalopin, a small leucine-rich repeat protein, in localizing the TRP melastatin 1 channel to retinal depolarizing bipolar cell dendrites. J Neurosci 31:10060–10066
Pinto LH, Vitaterna MH, Shimomura K, Siepka SM, Balannik V et al (2007) Generation, identification and functional characterization of the nob4 mutation of Grm6 in the mouse. Vis Neurosci 24:111–123
Pusch CM, Zeitz C, Brandau O, Pesch K, Achatz H et al (2000) The complete form of X-linked congenital stationary night blindness is caused by mutations in a gene encoding a leucine-rich repeat protein. Nat Genet 26:324–327
Rao A, Dallman R, Henderson S, Chen CK (2007) Gbeta5 is required for normal light responses and morphology of retinal ON-bipolar cells. J Neurosci 27:14199–14204
Ray TA, Heath KM, Hasan N, Noel JM, Samuels IS et al (2014) GPR179 is required for high sensitivity of the mGluR6 signaling cascade in depolarizing bipolar cells. J Neurosci 30:6334–6343
Scholl HP, Langrova H, Pusch CM, Wissinger B, Zrenner E, Apfelstedt-Sylla E (2001) Slow and fast rod ERG pathways in patients with X-linked complete stationary night blindness carrying mutations in the NYX gene. Invest Ophthalmol Vis Sci 42:2728–2736
Sergouniotis PI, Robson AG, Li Z, Devery S, Holder GE et al (2012) A phenotypic study of congenital stationary night blindness (CSNB) associated with mutations in the GRM6 gene. Acta Ophthalmol 90:e192–e197
Shen Y, Heimel JA, Kamermans M, Peachey NS, Gregg RG, Nawy S (2009) A transient receptor potential-like channel mediates synaptic transmission in rod bipolar cells. J Neurosci 29:6088–6093
Shim H, Wang CT, Chen YL, Chau VQ, Fu KG et al (2012) Defective retinal depolarizing bipolar cells in regulators of G protein signaling (RGS) 7 and 11 double null mice. J Biol Chem 287:14873–14879
van Genderen MM,B, Pearring JN et al (2009) Mutations in TRPM1 are a common cause of complete congenital stationary night blindness. Am J Hum Genet 85:730–736
Vardi N, Matesic DF, Manning DR, Liebman PA, Sterling P (1993) Identification of a G-protein in depolarizing rod bipolar cells. Vis Neurosci 10:473–478
Xu X, Li S, Xiao X, Wang P, Guo X, Zhang Q (2009) Sequence variations of GRM6 in patients with high myopia. Mol Vis 15:2094–2100
Xu Y, Dhingra A, Fina ME, Koike C, Furukawa T, Vardi N (2012) mGluR6 deletion renders the TRPM1 channel in retina inactive. J Neurophysiol 107:948–957
Zeitz C, Minotti R, Feil S, Matyas G, Cremers FP et al (2005a) Novel mutations in CACNA1F and NYX in Dutch families with X-linked congenital stationary night blindness. Mol Vis 11:179–183
Zeitz C, van Genderen M, Neidhardt J, Luhmann UF, Hoeben F et al (2005b) Mutations in GRM6 cause autosomal recessive congenital stationary night blindness with a distinctive scotopic 15-Hz flicker electroretinogram. Invest Ophthalmol Vis Sci 46:4328–4335
Zeitz C, Jacobson SG, Hamel CP, Bujakowska K, Neuille M et al (2013) Whole-exome sequencing identifies LRIT3 mutations as a cause of autosomal-recessive complete congenital stationary night blindness. Am J Hum Genet 92:67–75
Zhang Q, Xiao X, Li S, Jia X, Yang Z et al (2007) Mutations in NYX of individuals with high myopia, but without night blindness. Mol Vis 13:330–336
Zito I, Allen LE, Patel RJ, Meindl A, Bradshaw K et al (2003) Mutations in the CACNA1F and NYX genes in British CSNBX families. Hum Mutat 21:169
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Gregg, R., Ray, T., Hasan, N., McCall, M., Peachey, N. (2014). Interdependence Among Members of the mGluR6 G-protein Mediated Signalplex of Retinal Depolarizing Bipolar Cells. In: Martemyanov, K., Sampath, A. (eds) G Protein Signaling Mechanisms in the Retina. Springer Series in Vision Research, vol 3. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-1218-6_5
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