G-protein-coupled Receptors in Hearing Physiology

听力生理学中的 G 蛋白偶联受体

• 批准号: 7533109
• 负责人: Yong Lu
• 金额: $ 32.49万
• 依托单位: NORTHEAST OHIO MEDICAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-13 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7533109
• 关键词: Acoustic Nerve; Acoustics; Action Potentials; Acute; Affect; Agonist; Auditory; Auditory system; Bilateral; Birds; Brain; Brain Stem; CNS processing; Cell Nucleus; Cells; Chemical Agents; Chick Embryo; Chickens; Cochlear nucleus; Code; Complex; Computer information processing; Cues; Defect; Detection; Dyslexia; Education; Ensure; Family; Fire - disasters; Frequencies; G-Protein-Coupled Receptors; Glutamate Receptor; Glutamates; Glycine; Goals; Gramicidin; Hearing; Hearing problem; Integral Membrane Protein; Language Development; Localized; Maintenance; Mammals; Measures; Medial; Mediating; Metabotropic Glutamate Receptors; Molecular; Nervous system structure; Neurons; Neurotransmitters; Olives - dietary; Output; Pathway interactions; Pattern; Personal Satisfaction; Phase; Physiology; Play; Preparation; Presbycusis; Process; Quality of life; Regulation; Research; Role; Signal Transduction; Signal Transduction Pathway; Slice; Source; Speech; Stimulus; Synapses; Synaptic Transmission; System; Techniques; Testing; Therapeutic; Time; Tinnitus; Ursidae Family; Work; auditory nuclei; computerized data processing; dosage; drug development; feeding; gamma-Aminobutyric Acid; improved; neuronal cell body; neuronal excitability; patch clamp; prevent; receptor; receptor function; response; sound; sound frequency; tool; transmission process

DESCRIPTION (provided by applicant): Hearing defects are a significant societal problem in that they interfere with language development, education, and quality of life. Many defects result from dysfunctional central nervous system processing of auditory signals. G-protein-coupled receptors (GPCRs), the largest family of transmembrane proteins, are widespread and play important roles in the nervous system. Moreover, GPCRs are major common targets for new drug development. The long-term goal of this research is to understand the role of GPCRs associated with the two most prominent neurotransmitters, glutamate and GABA, in temporal processing in the auditory system, an important process that helps us to recognize and localize complex acoustic signals such as speech. Glutamate interacts with metabotropic glutamate receptors (mGluRs), and GABA with GABAB receptors (GABABRs), both of which are GPCRs. When activated, these receptors initiate a multitude of signaling transduction pathways important in mediating modulation of neuronal excitability and synaptic transmission (one of the major ways cells communicate with each other). Functions of these receptors in the auditory system are not well understood; this hinders drug development for treating hearing problems targeting these receptors. The primary focus of the present proposal is to determine how glutamate/mGluRs and GABA/GABABRs are involved in modulating synaptic transmission in auditory brainstem neurons that code temporal information of sounds. Our overall hypothesis is that mGluRs and GABABRs improve temporal processing in auditory brainstem neurons. We will use electrophysiological approaches (e.g., whole-cell and/or perforated patch recordings) combined with pharmacological tools (e.g. chemical agents that activate or suppress mGluRs and/or GABABRs) in acute brain slice preparations. Mechanisms whereby these receptors improve temporal processing in hearing will be revealed at cellular and molecular levels. The results of this work will further our understanding of how metabotropic receptors contribute to auditory signal processing/temporal coding, and help lay the groundwork for decisions about possible therapeutic approaches to hearing defects related to altered synaptic transmission, such as dyslexia, tinnitus, and age-related hearing loss.

描述（由申请人提供）：听力缺陷是一个重大的社会问题，因为它们会干扰语言发展，教育和生活质量。许多缺陷是由功能失调的中枢神经系统处理听觉信号引起的。最大的跨膜蛋白家族G蛋白偶联受体（GPCR）是广泛的，在神经系统中起着重要作用。此外，GPCR是新药开发的主要常见目标。这项研究的长期目标是了解与两个最突出的神经递质谷氨酸和GABA相关的GPCR在听觉系统中的时间处理中，这是一个重要过程，这是一个重要过程，该过程有助于我们识别和定位复杂的声学信号，例如演讲。谷氨酸与代谢型谷氨酸受体（MGLURS）和GABA与GABAB受体（GABABR）相互作用，这两种都是GPCR。激活后，这些受体会启动多种信号转导途径，这对于介导神经元兴奋性和突触传播的调节（细胞相互通信的主要方式之一）很重要。这些受体在听觉系统中的功能尚不清楚。这阻碍了药物开发用于治疗针对这些受体的听力问题。本建议的主要重点是确定谷氨酸/mglurs和gaba/gababr如何参与调节声音时间信息的听觉脑干神经元中的突触传播。我们的总体假设是mglurs和gababrs改善了听觉脑干神经元的时间处理。我们将使用电生理方法（例如全细胞和/或穿孔贴片记录）与急性脑切片制剂中的药理学工具（例如激活或抑制mglurs和/或Gababrs的化学剂）结合使用。这些受体在听力中改善时间处理的机制将在细胞和分子水平下显示。这项工作的结果将进一步了解我们对代谢受体如何促进听觉信号处理/时间编码的理解，并帮助为决定可能的治疗方法来为与突触变化有关的听力缺陷做出基础，例如阅读障碍，耳鸣和年龄，tinnitus和年龄 - 相关听力损失。