TRPM1: The endpoint of the mGluR6 signal transduction cascade in retinal ON-bipolar cells

Oregon Health and Science University, Ophthalmology, Portland, Oregon, USA.
BioEssays (Impact Factor: 4.73). 07/2010; 32(7):609-14. DOI: 10.1002/bies.200900198
Source: PubMed


For almost 30 years the ion channel that initiates the ON visual pathway in vertebrate vision has remained elusive. Recent findings now indicate that the pathway, which begins with unbinding of glutamate from the metabotropic glutamate receptor 6 (mGluR6), ends with the opening of the transient receptor potential (TRP)M1 cation channel. As a component of the mGluR6 signal transduction pathway, mutations in TRPM1 would be expected to cause congenital stationary night blindness (CSNB), and several such mutations have already been identified in CSNB families. Furthermore, expression of TRPM1 in both the retina and skin raises the possibility that a genetic link exists between certain types of visual and skin disorders.

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Available from: Catherine W Morgans, Apr 10, 2015
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    • "While rod-mediated vision is severely impaired in patients with cCSNB due to GRM6 mutations, their defi cits in visual acuity or other measures of cone-mediated vision are more variable and may be normal (Dryja et al., 2005 ; Zeitz et al., 2005 ; Godara et al., 2012 ; Sergouniotis et al., 2012 ; Bijveld et al., 2013 ). mGluR6 is the glutamate receptor used by depolarizing bipolar cells (DBCs; Masu et al., 1995 ), and GRM6 mutations impair vision when DBCs can no longer modulate transient receptor potential melastatin 1 (TRPM1) channel activity in response to changes in extracellular glutamate (Morgans et al., 2010 ). Our understanding of the impact of abnormal mGluR6 activity on retinal function has been expanding through the availability of mouse Grm6 mutants. "
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    ABSTRACT: Electroretinogram (ERG) studies identified a new mouse line with a normal a-wave but lacking the b-wave component. The ERG phenotype of this new allele, nob7, matched closely that of mouse mutants for Grm6, Lrit3, Trpm1, and Nyx, which encode for proteins expressed in depolarizing bipolar cells (DBCs). To identify the underlying mutation, we first crossed nob7 mice with Grm6 nob3 mutants and measured the ERGs in offspring. All the offspring lacked the b-wave, indicating that nob7 is a new allele for Grm6: Grm6 nob7 . Sequence analyses of Grm6 nob7 cDNAs identified a 28 base pair insertion between exons 8 and 9, which would result in a frameshift mutation in the open reading frame that encodes the metabotropic glutamate receptor 6 (Grm6). Sequencing both the cDNA and genomic DNA from exon 8 and intron 8, respectively, from the Grm6 nob7 mouse revealed a G to A transition at the last position in exon 8. This mutation disrupts splicing and the normal exon 8 is extended by 28 base pairs, because splicing occurs 28 base pairs downstream at a cryptic splice donor. Consistent with the impact of the resulting frameshift mutation, there is a loss of mGluR6 protein (encoded by Grm6) from the dendritic tips of DBCs in the Grm6 nob7 retina. These results indicate that Grm6 nob7 is a new model of the complete form of congenital stationary night blindness, a human condition that has been linked to mutations of GRM6.
    Visual Neuroscience 08/2015; 32:E004. DOI:10.1017/S0952523815000012 · 2.21 Impact Factor
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    • "Responses of photoreceptors and bipolar cells are reflected in ERG a- and b- waves, respectively. Unlike ionotropic GluRs on OFF bipolar cells, which are ion-permeable channels themselves, mGluR6 receptors on ON bipolar cells are G-protein coupled receptors that are separated from the channels that they gate [33]. Recently, TRPM1 has been identified to be the cation channel that is downstream to the mGluR6 cascade of ON bipolar cells [22,24]. "
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    ABSTRACT: Background Paraneoplastic retinopathy is caused by the cross-reaction of neoplasm-directed autoantibodies against retinal antigens and results in retinal damage. Paraneoplastic vitelliform retinopathy, a presumed paraneoplastic retinopathy with features of atypical melanoma-associated retinopathy, has recently been reported in patients with metastatic melanoma. Ocular ultrastructure and its autoantibody localization of paraneoplastic vitelliform retinopathy are still indefinable. This is the first report of anti-transient receptor potential M1 antibody directly against human retinal bipolar dendritic tips in a melanoma patient with paraneoplastic vitelliform retinopathy. Case presentation We present a pair of postmortem eyes of an 80-year-old male with metastatic cutaneous melanoma, who developed paraneoplastic vitelliform retinopathy. The autopsied eyes were examined with light microscopy, immunohistochemistry, and transmission electron microscopy. Microscopically, the inner nuclear layer and outer plexiform layer were the most affected retinal structures, with local thinning. The lesions extended to the outer nuclear layer, resulting in focal retinal degeneration, edema, and atrophy. No active inflammation or melanoma cells were observed. Immunohistochemistry showed tightly compact bipolar cell nuclei (protein kinase C alpha/calbindin positive) with blur/loss of ON bipolar cell dendritic tips (transient receptor potential M1 positive) in diffusely condensed outer plexiform layer. The metastatic melanoma cells in his lung also showed immunoreactivity against transient receptor potential M1 antibody. Transmission electron microscopy illustrated degenerated inner nuclear layer with disintegration of cells and loss of cytoplasmic organelles. These cells contained many lysosomal and autophagous bodies and damaged mitochondria. Their nuclei appeared pyknotic and fragmentary. The synapses in the outer plexiform layer were extensively degenerated and replaced with empty vacuoles and disintegrated organelles. Conclusion This case provides a convincing histological evidence of melanoma-associated autoantibodies directly against transient receptor potential M1 channels that target the ON bipolar cell structures in the inner nuclear and outer plexiform layers in paraneoplastic vitelliform retinopathy.
    BMC Ophthalmology 11/2012; 12(1):56. DOI:10.1186/1471-2415-12-56 · 1.02 Impact Factor
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    • "Hyperpolarization is conserved in horizontal and hyperpolarizing bipolar cells as a result of postsynaptic ionotropic glutamate receptors. In contrast, photoreceptor hyperpolarization is inverted in depolarizing bipolar cells (DBCs) as a result of a decrease in activation of postsynaptic metabotropic glutamate receptor 6 (GRM6) and subsequent opening of a transient receptor potential melastatin 1 protein (TRPM1)-containing cation-selective channel (Koike et al. 2010a, 2010b; Morgans et al. 2009, 2010; Shen et al. 2009; Shiells et al. 1981; Slaughter and Miller 1981). Mutations in several genes disrupt photoreceptor-to-DBC synaptic transmission. "
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    ABSTRACT: Mutations in TRPM1 are found in humans with an autosomal recessive form of complete congenital stationary night blindness (cCSNB). The Trpm1(-/-) mouse has been an important animal model for this condition. Here we report a new mouse mutant, tvrm27, identified in a chemical mutagenesis screen. Genetic mapping of the no b-wave electroretinogram (ERG) phenotype of tvrm27 localized the mutation to a chromosomal region that included Trpm1. Complementation testing with Trpm1(-/-) mice confirmed a mutation in Trpm1. Sequencing identified a nucleotide change in exon 23, converting a highly conserved alanine within the pore domain to threonine (p.A1068T). Consistent with prior studies of Trpm1(-/-) mice, no anatomical changes were noted in the Trpm1(tvrm27/tvrm27) retina. The Trpm1(tvrm27/tvrm27) phenotype is distinguished from that of Trpm1(-/-) by the retention of TRPM1 expression on the dendritic tips of depolarizing bipolar cells (DBCs). While ERG b-wave amplitudes of Trpm1(+/-) heterozygotes are comparable to WT, those of Trpm1(+/tvrm27) mice are reduced by 32%. A similar reduction in the response of Trpm1(+/tvrm27) DBCs to LY341495 or capsaicin is evident in whole cell recordings. These data indicate that the p.A1068T mutant TRPM1 acts as a dominant negative with respect to TRPM1 channel function. Further, these data indicate that the number of functional TRPM1 channels at the DBC dendritic tips is a key factor in defining DBC response amplitude. The Trpm1(tvrm27/tvrm27) mutant will be useful for elucidating the role of TRPM1 in DBC signal transduction, for determining how Trpm1 mutations impact central visual processing, and for evaluating experimental therapies for cCSNB.
    Journal of Neurophysiology 08/2012; 108(9). DOI:10.1152/jn.00137.2012 · 2.89 Impact Factor
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