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: 4.84). 07/2010; 32(7):609-14. DOI: 10.1002/bies.200900198
Source: PubMed

ABSTRACT 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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    • "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 · 3.04 Impact Factor
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    • "When glutamate activates mGluR6 on these cells in the dark, the heterotrimeric G-protein, G o , becomes active. Active G o then closes the non-selective cation channel TRPM1 via an unidentified mechanism (reviewed by Koike et al., 2010a; Morgans et al., 2010). The dominant α-subunit of G o is Gα o1 , but Gα o2 also contributes to the light response (Dhingra et al., 2000; Dhingra et al., 2002; Okawa et al., 2010). "
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    ABSTRACT: 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. In the ON bipolar cells, mGluR6 inverts the photoreceptor's signal via a cascade in which glutamate released from photoreceptors closes the TRPM1 channel. This cascade is essential for vision since deficiencies in its proteins lead to complete congenital stationary night blindness. Here we report that Gβ(3) participates in the G-protein heterotrimer that couples mGluR6 to TRPM1. Gβ(3) deletion in mouse greatly reduces the light response under both scotopic and photopic conditions, but it does not eliminate it. In addition, Gβ(3) deletion causes mislocalization and downregulation of most cascade elements and modulators. Furthermore, Gβ(3) may play a role in synaptic maintenance since in its absence, the number of invaginating rod bipolar dendrites is greatly reduced, a deficit that was not observed at 3 weeks, the end of the developmental period.
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 08/2012; 32(33):11343-55. DOI:10.1523/JNEUROSCI.1436-12.2012 · 6.75 Impact Factor
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    • "The processes in the presynaptic photoreceptor terminals that involve EF-hand-containing proteins, including distinct neuronal Ca 2+ -sensor (NCS) -proteins and Ca 2+ -binding proteins (CaBPs), will be summarized in the present review. Postsynaptic activity-dependent signaling is covered by other recent reviews (Burgoyne, 2007; Koike et al., 2010; Morgans et al., 2010). "
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    ABSTRACT: Photoreceptors, the light-sensitive receptor neurons of the retina, receive and transmit a plethora of visual informations from the surrounding world. Photoreceptors capture light and convert this energy into electrical signals that are conveyed to the inner retina. For synaptic communication with the inner retina, photoreceptors make large active zones that are marked by synaptic ribbons. These unique synapses support continuous vesicle exocytosis that is modulated by light-induced, graded changes of membrane potential. Synaptic transmission can be adjusted in an activity-dependent manner, and at the synaptic ribbons, Ca(2+)- and cGMP-dependent processes appear to play a central role. EF-hand-containing proteins mediate many of these Ca(2+)- and cGMP-dependent functions. Since continuous signaling of photoreceptors appears to be prone to malfunction, disturbances of Ca(2+)- and cGMP-mediated signaling in photoreceptors can lead to visual defects, retinal degeneration (rd), and even blindness. This review summarizes aspects of signal transmission at the photoreceptor presynaptic terminals that involve EF-hand-containing Ca(2+)-binding proteins.
    Frontiers in Molecular Neuroscience 02/2012; 5:26. DOI:10.3389/fnmol.2012.00026 · 4.08 Impact Factor
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