Molecular Basis of Somatic Sensation

描述(申请人提供)：机械转导是细胞将机械力转换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，并向本体感觉、触摸和疼痛发出信号。无论是在生理上还是在分子水平上，这些都是最不被理解的感觉之一。为了找到一种可能在哺乳动物中介导皮肤机械感觉的离子通道，我们在蠕虫中寻找了介导这种感觉的退化离子通道的同源物。我们发现了一个由DRG神经元表达的BnaC1apha，它向远端运输，而不是中枢性运输，并且特异地定位于皮肤感觉末梢。缺乏BNaC1的突变动物的触摸敏感度降低，这表明BNaC1是机械感觉通道的一部分。机械感觉DRG神经元中的BNaC1pha与相关蛋白DRASIC和/或BNaC2/ASIC形成异多聚体。最近，我们还发现了一种可能的支架蛋白(PICK1)，它与BNaClα结合，存在于触摸终端中，因此可能是触摸机械转导复合体的附加成分。我们现在需要知道BnaC1pha和PICK1是否可能参与本体感觉末端器官(如肌梭)以及高频环状小体的机械感觉。我们将用抗BnaC1pha和PICK1的抗体进行测试。我们需要了解BnaC1pha(也许还有PICK1)从DRG细胞体到外围的定向运输，这是DRG中一种新的蛋白质分选模式。我们将使用带有标记的BnaC1pha的DRG病毒转染法，并突变其胞内结构域以影响其转运。外周靶向结构域可能与其他感觉蛋白共享。最后，我们需要确定触摸传导复合体的其他潜在元件，并将通过鉴定来自体感神经节的蛋白质来做到这一点，这些蛋白质(1)结合BNaC1pha、DRASIC或BNaC2/ASIC，或(2)与其他触摸所需的线虫蛋白同源。这些研究将有助于阐明触摸、本体感觉和某些形式的疼痛的机械转导的分子机制。

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.