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觉毛细胞提供关于头部位置和 神经元信号的运动。本研究的目的是阐明其分子机制 从前庭毛细胞到传入纤维的潜在突触传递。传入毛细胞 突触表现出解剖（突触体或带）和功能（响应分级的 去极化）的专门化，使其区别于神经系统中的其他突触。我们这里 我建议研究哪些蛋白质和蛋白质相互作用在传统的突触中是重要的 对毛细胞突触传递很重要此外，前庭生理学缺乏， 了解I型和II型毛细胞之间的功能差异。I型毛细胞，只在 突触被传入神经吞噬，表明突触生理学的差异。拟议 因此，实验进一步旨在了解分子和功能差异， 前庭I型和II型毛细胞之间的神经递质释放。这些实验将进一步促进我们的 前庭和听觉系统第一突触的分子和生物物理学理解。 毛细胞从细胞体的基底外侧端释放神经递质，提供相对容易的通路 用于引入毒素和肽以急性扰乱蛋白质功能的突触区域。胞吐 将通过测量囊泡融合时细胞膜面积的增加来直接监测 与细胞膜结合。特异性目的1检验了胞吐作用由特异性 SNARE蛋白的一个子集。具体目标2解决囊泡再循环是否限制胞吐作用。在 具体目标3验证谷氨酸在正反馈回路中起作用以增强释放的假设 尤其是I型毛细胞。详细了解蛋白质和机制的释放，在这个 初始感觉突触有助于确定针对前庭功能障碍新治疗方法。