The role of nyctalopin in the mammalian retina

    Project: Research project

    Description

    DESCRIPTION (provided by applicant): Complete X-linked congenital stationary night blindness (CSNB1) is a hereditary disease caused by a block in synaptic transmission in the retina between photoreceptors and ON-bipolar cells (ON-BPCs). Photoreceptors release the neurotransmitter, glutamate, in darkness, and reduce the rate of release in response to light. ON-BPCs respond to glutamate via the mGluR6 metabotropic glutamate receptor. Binding of glutamate by mGluR6 leads to the closure of a cation channel and hyperpolarization of the ON-BPC. The role of mGluR6 in transducing the action of glutamate in the ON-BPC dendrites is central to vertebrate vision, yet the steps in the mGluR6 signaling pathway are poorly understood, and the molecular identity of the ON-BPC cation channel is unknown. The human gene responsible for CSNB1, NYX, encodes a novel protein, nyctalopin, belonging to the family of leucine rich repeat (LRR) proteins. A mouse mutant, nob (no b-wave) has a similar phenotype to CSNB1 and a deletion in the nyx gene. Expression of mGluR6 appears normal in the nob mice, however their ON-BPCs fail to respond to exogenously applied glutamate, implicating nyctalopin in the mGluR6 signaling pathway. Although essential for the ON-BPC light response, the cellular function of nyctalopin is not known. Related LRR proteins in the nervous system have been implicated in neurite outgrowth and synapse formation, where they bind other proteins through their LRR domains including soluble ligands, receptors, and G proteins. We propose that nyctalopin is found at the photoreceptor to ON-BPC synapse where it interacts with components of the mGluR6 signaling pathway. To test this hypothesis, we will determine the localization of nyctalopin in the retina by immunofluorescence microscopy and immuno-electron microscopy using antibodies directed against a unique nyctalopin peptide. We will identify proteins interacting with nyctalopin by immunoprecipitation and yeast two-hybrid screening. These results will provide insight into the role of nyctalopin in synaptic transmission between photoreceptors and ON-BPCs in the retina, and may lead to the identification of other components of the ON-BPC pathway.
    StatusFinished
    Effective start/end date9/1/057/31/07

    Funding

    • National Institutes of Health: $74,946.00
    • National Institutes of Health: $76,250.00

    Fingerprint

    Retina
    Glutamic Acid
    Synaptic Transmission
    Synapses
    Cations
    Light
    Inborn Genetic Diseases
    Metabotropic Glutamate Receptors
    Proteins
    Immunoelectron Microscopy
    Darkness
    Dendrites
    metabotropic glutamate receptor 6
    Fluorescence Microscopy
    GTP-Binding Proteins
    Immunoprecipitation
    Leucine
    Nervous System
    Genes
    Neurotransmitter Agents

    ASJC

    • Medicine(all)