Pharmacology of Neurotransmitters in Hair Cell Organs

毛细胞器官中神经递质的药理学

• 批准号: 7455305
• 负责人: WILLIAM F SEWELL
• 金额: $ 30.75万
• 依托单位: MASSACHUSETTS EYE AND EAR INFIRMARY
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-12-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7455305
• 关键词: 2-hydroxyacid dehydrogenase; AMPA Receptors; Achievement; Acoustic Nerve; Acoustic Stimulation; Affect; Auditory; Biochemical; Biological; Biological Assay; Calcium; Characteristics; Chromosome Pairing; Cochlea; Code; Condition; Coupled; Crystallography; Disease; Elements; Endocytosis; Enzymes; Excitatory Amino Acid Antagonists; Exocytosis; Fiber; Frequencies; Furosemide; Glutamate Receptor; Glutamates; Goals; Hair Cells; Homer protein; Hydroxy Acids; Immunohistochemistry; Isomerism; Keto Acids; Kinetics; Laboratories; Lead; Link; Location; Mediating; Membrane; Meniere' s Disease; Metabotropic Glutamate Receptors; Monitor; Mus; N-Methylaspartate; Nerve Fibers; Neurons; Neurotransmitters; Nicotinamide adenine dinucleotide; Numbers; Organ; Oxidoreductase; Pharmaceutical Preparations; Pharmacology; Play; Process; Proteins; Range; Regulation; Research Personnel; Role; Ryanodine Receptor Calcium Release Channel; Stimulus; Structure; Surface; Synapses; Synaptic Membranes; Synaptic Transmission; Testing; Time; Tinnitus; Trauma; Vesicle; Western Blotting; Work; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; amino 3 hydroxy 5 methylisoxazole 4 propionate; auditory stimulus; base; capsule; design; enzyme substrate; in vivo; insight; interest; neurotransmission; receptor; receptor coupling; response; ribbon synapse; transmission process

DESCRIPTION (provided by applicant): Our long-term goals are centered on understanding synaptic transmission and neurotransmitters in the cochlea. In this project period, we will focus on dynamic regulation of afferent transmission and its role in achieving some of the remarkable characteristics of auditory stimulus coding. The temporal precision and dynamic range encoded in auditory neurons is astonishing when one considers that this process is mediated by the hair cell releasing packets of neurotransmitter and that the entire input to the auditory nerve fiber is encoded in a single synapse. The achievement of these stimulus coding capabilities in a single synapse requires a number of specializations, not the least of which must be some formidable mechanisms to regulate synaptic strength over time. We will apply recent advances in understanding glutamatergic synapses in the CMS to examine dynamic regulation of auditory transmission. First (aim 1), we will explore the hypothesis that the presence of glutamate (AMPA) receptors in the synaptic membrane of auditory neurons is dynamically regulated, and will focus on the roles of activation of NMDA and metabotropic glutamate receptors in this phenomenon. Work in our laboratory indicates robust regulation of AMPA receptors in auditory neurons. Second (aim 2), we will examine the hypothesis that transmitter release may be regulated through activation of metabotropic glutamate receptors coupled to calcium-induced calcium release. Finally (aim 3), we will explore the biochemical implications for auditory transmission of the surprising recent finding that the major protein in the synaptic ribbon, an unusual structure associated with the afferent synapse on the hair cell, is a functional enzyme, an NAD dependent, D isomer specific 2 hydroxyacid dehydrogenase. Understanding how synaptic strength is regulated may aid in developing treatments for disorders in which these regulatory mechanism may be evoked, such as excitotoxic responses to trauma, tinnitus, and Meniere's syndrome. This work could provide a scientific basis for evaluating and modifying drug treatments for those problems. Last, but not least, because the demands on synaptic transmission for auditory coding far exceed those at any other synapse, it should not be surprising that several interesting facets of neurotransmission are highly developed in the cochlea. Examples include adaptations of the AMPA receptor for temporal precision and of transmitter release mechanisms for fine control of graded release. Mechanisms for dynamic and precise regulation of synaptic strength may be yet another instance in which basic biological machinery is highly adapted for auditory processing. If so, then analysis and understanding of these phenomena in auditory neurons could ultimately lead to insight useful in understanding CNS transmission.

描述（由申请人提供）：我们的长期目标集中在了解耳蜗中的突触传播和神经递质。在这个项目时期，我们将重点介绍传入传播的动态调节及其在实现听觉刺激编码的一些显着特征中的作用。当一个人认为该过程是由毛细单元介导的神经递质数据包介导的，并且对听觉神经纤维的整个输入介导的，在听觉神经元中编码的时间精度和动态范围令人惊讶。单个突触中这些刺激编码功能的实现需要许多专业，其中最重要的是必须是某种强大的机制来调节突触强度随着时间的流逝。我们将采用最近的进步来理解CMS中的谷氨酸能突触以检查听觉传播的动态调节。首先（AIM 1），我们将探讨一个假说，即听觉神经元突触膜中谷氨酸（AMPA）受体的存在是动态调节的，并且将集中于这种现象中NMDA和代替谷氨酸受体的激活作用。在我们的实验室中的工作表明对听觉神经元中AMPA受体的强大调节。第二（AIM 2），我们将研究以下假设：释放可以通过激活与钙诱导的钙释放的代谢型谷氨酸受体的激活来调节。最后（AIM 3），我们将探讨令人惊讶的最近发现的听觉传播的生化含义，即突触色带中的主要蛋白质是一种与毛细胞上传入突触相关的异常结构，是一种功能性酶，是一种NAD依赖性，依赖于Disomer disomer特异性2羟基脱氢酶。了解如何调节突触强度可能有助于开发可能引起这些调节机制的疾病的治疗方法，例如对创伤，耳鸣和Meniere综合征的兴奋性毒性反应。这项工作可以为评估和修改这些问题的药物治疗提供科学依据。最后但并非最不重要的一点是，因为对听觉编码的突触传输的需求远远超过了其他突触的要求，因此在耳蜗中高度发展了神经传递的几个有趣的方面，这也就不足为奇了。例子包括适应AMPA受体的时间精度和发射机释放机制，以精细控制分级释放。动态和精确调节突触强度的机制可能是另一个实例，其中基本的生物机械高度适用于听觉处理。如果是这样，那么对听觉神经元中这些现象的分析和理解最终可能会导致有用的洞察力，可用于理解中枢神经系统的传播。