G-protein-coupled Receptors in Hearing Physiology

描述（由申请人提供）：听力缺陷是一个重要的社会问题，因为它们会干扰语言发展，教育和生活质量。许多缺陷是由于中枢神经系统对听觉信号的处理功能障碍造成的。G蛋白偶联受体（GPCR）是最大的跨膜蛋白家族，分布广泛，在神经系统中发挥重要作用。此外，GPCR是新药开发的主要共同靶标。这项研究的长期目标是了解与两种最重要的神经递质谷氨酸和GABA相关的GPCR在听觉系统时间处理中的作用，这是一个重要的过程，有助于我们识别和定位复杂的声学信号，如语音。谷氨酸与代谢型谷氨酸受体（mGluR）相互作用，GABA与GABAB受体（GABABR）相互作用，两者都是GPCR。当被激活时，这些受体启动多种信号转导途径，这些途径在介导神经元兴奋性和突触传递的调节（细胞相互通信的主要方式之一）中很重要。这些受体在听觉系统中的功能尚未得到很好的理解;这阻碍了针对这些受体治疗听力问题的药物开发。本提案的主要重点是确定谷氨酸/mGluRs和GABA/GABABR如何参与调制听觉脑干神经元编码声音的时间信息的突触传递。我们的总体假设是，mGluRs和GABABR改善听觉脑干神经元的时间处理。我们将使用电生理学方法（例如，全细胞和/或穿孔斑片记录）与药理学工具（例如激活或抑制mGluR和/或GABABR的化学试剂）组合。这些受体改善听觉时间处理的机制将在细胞和分子水平上揭示。这项工作的结果将进一步了解代谢型受体如何有助于听觉信号处理/时间编码，并有助于为与突触传递改变相关的听力缺陷（如阅读障碍，耳鸣和年龄相关的听力损失）的可能治疗方法奠定基础。

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.