Molecular Basis of Somatic Sensation

体感的分子基础

• 批准号: 6862727
• 负责人: Jaime Garcia-Anoveros
• 金额: $ 27.71万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-03-01 至 2008-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6862727
• 关键词: gene expression; genetically modified animals; immunocytochemistry; laboratory mouse; laboratory rat; mass spectrometry; mechanoreceptors; nerve endings; neurogenetics; nucleoproteins; polymerase chain reaction; proprioception /kinesthesia; protein protein interaction; psychophysiology; sensation; sensorimotor system; sensory mechanism; sensory signal detection; somatic afferent nerve; touch; transfection /expression vector; yeast two hybrid system

DESCRIPTION (provided by applicant): Mechanotransduction is the process whereby a cell transforms a mechanical force into an electrochemical signal. For instance, somatosensory neurons of the dorsal root and trigeminal ganglia detect deformations to the body and signal the senses of proprioception touch and pain. These are among the least understood senses, both at the physiological and at the molecular level. To find an ion channel that might mediate cutaneous mechanosensation in mammals, we looked for homologs of the degenerin ion channels that mediate this sense in worms. We found one, BnaC1apha that is expressed by DRG neurons, is transported distally but not centrally, and is specifically located in cutaneous sensory endings. Mutant animals lacking BNaC1 have reduced touch sensitivity, suggesting that BNaC1 is part of the mechanosensory channel. BnaC1alpha in mechanosensory DRG neurons forms heteromultimers with the related proteins DRASIC and/or BNaC2/ASIC. Recently, we also found a putative scaffolding protein (PICK1) that binds to BnaCl alpha, is present in touch terminals, and thus may be an additional component of a mechanotransducing complex for touch. We now need to know whether BnaC1alpha and PICK1 might be involved in mechanosensation in proprioceptive end organs such as muscle spindles as well as in the high frequency Pacinian corpuscles. We will test this with antibodies against BnaC1alpha and PICK1. We need to understand the directional transport of BnaC1alpha (and perhaps PICK1) from DRG cell bodies to the periphery, a novel mode of protein sorting in DRG. We will use viral transfection of DRG with tagged BnaC1alpha, and mutate its intracellular domains to affect its transport. A peripheral targeting domain might be shared with other sensory proteins. Finally, we need to identify other potential elements of the touch transduction complex, and will do so by identifying proteins from somatosensory ganglia that (1) bind BnaC1alpha, DRASIC, or BNaC2/ASIC, or (2) are homologous to other nematode proteins necessary for touch. These studies will help elucidate the molecular mechanisms for mechanotransduction in touch, proprioception, and certain forms of pain.

描述（由申请人提供）：机械转导是细胞将机械力转化为电化学信号的过程。例如，背根和三叉神经节的体感神经元检测身体的变形并发出本体感觉、触觉和疼痛的信号。无论是在生理水平还是在分子水平上，这些都是最难理解的感觉。为了找到可能介导哺乳动物皮肤机械感觉的离子通道，我们寻找了介导蠕虫中这种感觉的简并蛋白离子通道的同源物。我们发现了一种由 DRG 神经元表达的 BnaC1apha，它向远端转运，但不向中枢转运，并且专门位于皮肤感觉末梢。缺乏 BNaC1 的突变动物的触觉敏感性降低，表明 BNaC1 是机械感觉通道的一部分。机械感觉 DRG 神经元中的 BnaC1α 与相关蛋白 DRASIC 和/或 BNaC2/ASIC 形成异多聚体。最近，我们还发现了一种与 BnaCl α 结合的推定支架蛋白 (PICK1)，存在于触摸终端中，因此可能是触摸机械传导复合物的附加成分。我们现在需要知道 BnaC1alpha 和 PICK1 是否可能参与本体感觉终末器官（如肌梭）以及高频 Pacinian 小体的机械感觉。我们将使用针对 BnaC1alpha 和 PICK1 的抗体对此进行测试。我们需要了解 BnaC1alpha（也许还有 PICK1）从 DRG 细胞体到外周的定向转运，这是 DRG 中蛋白质分选的一种新模式。我们将使用带有 BnaC1alpha 标记的 DRG 进行病毒转染，并突变其胞内结构域以影响其运输。外周靶向结构域可能与其他感觉蛋白共享。最后，我们需要识别触觉转导复合体的其他潜在元件，并且将通过识别来自体感神经节的蛋白质来实现这一点，这些蛋白质（1）结合 BnaC1alpha、DRASIC 或 BNaC2/ASIC，或（2）与其他必要的线虫蛋白质同源用于触摸。这些研究将有助于阐明触觉、本体感觉和某些形式的疼痛的机械传导的分子机制。