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Regulation of kainate receptor expression in cone bipolar cells

视锥双极细胞中红藻氨酸受体表达的调节

基本信息

批准号：
10367733
负责人：
Anis Contractor
金额：
$ 43.44万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-30 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10367733
关键词：
AMPA Receptors Acids Acute Address Adult Affinity Anatomy Area Autoimmune Diseases Binding Brain CRISPR/Cas technology Cell Culture Techniques Cells Chief Cell Communication Cone Contractor Data Databases Development Epilepsy Excision Excitatory Synapse Frequencies Genetic Diseases Glutamate Receptor Glutamates Health Human Individual Interneurons Kainic Acid Receptors Kinetics Knock-out Light Measures Mediating Metabotropic Glutamate Receptors Microscopy Modality Modification Molecular Molecular Genetics Mood Disorders Mus Pathway interactions Perfusion Pharmaceutical Preparations Photoreceptors Physiologic pulse Physiological Play Primates Process Property Proteins Proteomics RNA Splicing Receptor Cell Recovery Regulation Resolution Retina Retinal Cone Role Signal Transduction Spermophilus Structure Synapses System Vision Work authority base cell type desensitization experimental study genetic manipulation in vivo kainate mouse model outer plexiform layer pain signal preservation receptor receptor expression receptor function response tool transcriptomics virus genetics visual information

项目摘要

The long term objective of this work is to understand the molecular genetic basis for how the retina transmits and processes the signals produced when lights are turned off. Cone photoreceptors mediate vision during daylight and use glutamate as their transmitter. The cone signals are carried across the retina by two functional classes of bipolar cells, On and Off, which have different glutamate receptors that cause them to depolarize (ie, signal) either at light-on or -off, respectively. Each functional class of bipolar cell can be subdivided into 5-6 anatomical types. This study focuses on the Off bipolar cells that chiefly express sign-preserving kainate-type glutamate receptors (subunits GluK1-5). Surprisingly, while AMPA receptors predominate at most CNS synapses, kainate receptors predominate at the cone synapses of most of the Off bipolar cell types. They are important to study for at least four reasons. First, the temporal signaling properties of kainate receptors differ from those of AMPA receptors, and these differences are likely to change the size and timing of the Off signals traversing the retina in as yet poorly understood ways. Second, the kainate receptors at most well-studied synapses almost always contain the GluK2 subunit, whereas the Off bipolar cells choose the less well-studied GluK1 subunit as their main subunit instead. Third, Off bipolar cells express Neto1, an auxiliary receptor subunit that profoundly alters the in vivo responses of GluK2-containing receptors. The effect of Neto1 on endogenous GluK1-containing receptors has not yet been studied. And fourth, while the functional properties of different kainate receptors on the Off bipolar cell have been described, the molecular basis for their diverse responses has not been established. To determine the subunit basis for signaling at the Off bipolar cell synapse, we propose to study synaptic responses in mice in which receptor subunits (GluK1-GluK5) are individually knocked out either permanently or acutely. Similar studies will be performed to define the role of the auxiliary subunit Neto1 in communication. Three specific aims will 1) determine the subunits that mediate synaptic responses in Off bipolar cell types 1a, 2, and 3a; 2) determine the function of Neto proteins in signaling at the Off bipolar cell synapse; and, 3) determine the physiological function of the GluK1-1d subunit, which is unique to the retina, the molecular factors that localize the GluK1-1d subunit to the synapse.

这项工作的长期目标是了解视网膜的分子遗传学基础