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递和神经递质。在这个项目期间，我们将重点关注传入传输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。当人们认为这一过程是由毛细胞释放神经递质包介导的，并且听觉神经纤维的整个输入被编码在单个突触中时，听觉神经元中编码的时间精度和动态范围是惊人的。在单个突触中实现这些刺激编码能力需要许多专门化，其中最重要的是必须是一些强大的机制来随着时间的推移调节突触强度。我们将应用理解 CMS 中谷氨酸突触的最新进展来检查听觉传输的动态调节。首先（目标 1），我们将探讨听觉神经元突触膜中谷氨酸 (AMPA) 受体的存在受到动态调节的假设，并将重点关注 NMDA 和代谢型谷氨酸受体的激活在此现象中的作用。我们实验室的工作表明听觉神经元中 AMPA 受体的强大调节。其次（目标 2），我们将检验递质释放可能通过代谢型谷氨酸受体的激活与钙诱导的钙释放相结合来调节的假设。最后（目标 3），我们将探讨最近令人惊讶的发现对听觉传递的生化影响，即突触带（与毛细胞传入突触相关的不寻常结构）中的主要蛋白质是一种功能酶，是一种 NAD 依赖性酶，D异构体特异性2羟酸脱氢酶。了解突触强度如何调节可能有助于开发针对可能引发这些调节机制的疾病的治疗方法，例如对创伤、耳鸣和梅尼埃综合症的兴奋毒性反应。这项工作可以为评估和修改针对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，由于听觉编码对突触传递的需求远远超过任何其他突触，因此神经传递的几个有趣方面在耳蜗中高度发达也就不足为奇了。例子包括对 AMPA 受体进行调整以实现时间精度，以及对递质释放机制进行调整以实现分级释放的精细控制。动态和精确调节突触强度的机制可能是基本生物机制高度适应听觉处理的另一个例子。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带来有助于理解中枢神经系统传递的见解。