Molecular mechanisms of vestibular hair cell exocytosis

前庭毛细胞胞吐作用的分子机制

• 批准号: 7628704
• 负责人: FELIX E SCHWEIZER
• 金额: $ 0.69万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7628704
• 关键词: Address; Affect; Anatomy; Area; Auditory; Auditory system; Biology; Birds; Calcium; Calcium Channel; Cell membrane; Cells; Characteristics; Chromosome Pairing; Class; Clathrin; Complex; Cytoplasm; Electric Capacitance; Elements; Endocytosis; Exhibits; Exocytosis; Feedback; Fiber; Fire - disasters; Foundations; Frequencies; Functional disorder; Glutamates; Goals; Grant; Hair; Hair Cells; Head; Human; Knowledge; Mammals; Measures; Mechanics; Mediating; Membrane Fusion; Membrane Potentials; Metabotropic Glutamate Receptors; Molecular; Monitor; Movement; Nerve; Nerve Endings; Nervous system structure; Neuraxis; Neurons; Output; Pattern; Peptides; Photoreceptors; Physiology; Positioning Attribute; Principal Investigator; Property; Protein Isoforms; Proteins; Purpose; Range; Recycling; Regulation; Reptiles; Research; Research Personnel; Retina; Rodent; SNAP receptor; Sensory; Sensory Hair; Signal Pathway; Signal Transduction; Stimulus; Synapses; Synaptic Transmission; Synaptic Vesicles; System; Testing; Toxin; Translating; Type I Hair Cell; Type II Hair Cell; VAMP-1; Vertebrates; Vesicle; Vestibular Hair Cells; Work; afferent nerve; insight; neuronal cell body; neurotransmitter release; novel; novel therapeutics; presynaptic; programs; protein function; protein protein interaction; receptor; research study; response; sensory system; synaptotagmin; syntaxin

Mechanosensory hair cells in the vestibular system transduce information about head position and movement into neuronal signals. The aim of this proposal is to elucidate the molecular mechanisms underlying synaptic transmission from vestibular hair cells to afferent fibers. The hair cells afferent synapse exhibits anatomical (synaptic bodies or ribbons) and functional (responding to graded depolarizations) specializations that distinguish them from other synapses in the nervous system. We here propose to investigate which proteins and protein-interactions important at conventional synapses are important for hair cell synaptic transmission. Furthermore, vestibular physiology lacks and understanding of the functional difference between type I and type II hair cells. Type I hair cells, found only in amniotes, are engulfed by the afferent nerve, suggesting differences in synaptic physiology. The proposed experiments are therefore further aimed at understanding the molecular and functional difference in neurotransmitter release between vestibular type I and type II hair cells. These experiments will further our molecular and biophysical understanding of the first synapse in the vestibular and auditory system. Hair cells release neurotransmitter from the basolateral end of the cell body, offering relatively easy access to synaptic areas for the introduction of toxins and peptides to acutely perturb protein function. Exocytosis will be monitored directly by measuring the increase in cell membrane area that occurs when vesicles fuse with the plasma membrane. Specific Aim 1 tests the hypothesis that exocytosis is regulated by a specific subset of SNARE proteins. Specfic Aim 2 addresses whether vesicle recycling is limiting for exocytosis. In Specific Aim 3 the hypothesis is tested that glutamate acts in a positive feedback loop to enhance release especially in type I hair cells. A detailed understanding of the proteins and mechanisms of release at this initial sensory synapse aid in identifying novel therapeutic approaches targeting vestibular dysfunction.

前庭系统中的机械感力毛细胞传导有关头部位置和 移动到神经元信号。该建议的目的是阐明分子机制 从前庭毛细胞到传入纤维的潜在突触传播。毛细胞传入 突触表现出解剖学（突触体或丝带）和功能性（对等级响应 去极化）专门将它们与神经系统中的其他突触区分开。我们在这里 建议研究哪些蛋白质和蛋白质相互作用在常规突触中很重要 对于毛细胞突触传播很重要。此外，前庭生理缺乏 了解I型和II型毛细胞之间的功能差异。 I型毛细胞，仅在 羊膜被传入神经吞没，表明突触生理的差异。提议 因此，实验旨在了解分子和功能差异 神经递质I型和II型毛细胞之间的释放。这些实验将进一步 对前庭和听觉系统中第一个突触的分子和生物物理理解。 毛细胞从细胞体的基底外侧释放神经递质，提供相对容易的访问 将毒素和肽引入急性扰动蛋白功能的突触区域。胞吞作用 将通过测量囊泡融合时直接测量细胞膜区域的增加来监测 与质膜。特定的目标1检验了胞吐作用的假设受到特定的调节 核心蛋白的子集。 SpecFic AIM 2解决了囊泡回收是否限制了胞吐作用。在 特定目的3检验了假设谷氨酸在正反馈循环中起作用以增强释放 特别是在I型毛细胞中。对此详细了解蛋白质和释放机制 最初的感觉突触有助于识别针对前庭功能障碍的新型治疗方法。