Molecular Basis of Somatic Sensation

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到身体的变形，并发出本体感觉、触觉和疼痛的信号。无论是在生理上还是在分子水平上，这些都是最不为人所知的感觉。为了找到一种可能介导哺乳动物皮肤机械感觉的离子通道，我们在蠕虫中寻找介导这种感觉的变性离子通道的同系物。我们发现了一种由DRG神经元表达的BnaC1apha，它被远端转运而不是中央转运，并且特异性地位于皮肤感觉末梢。缺乏BNaC1的突变动物的触觉敏感性降低，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bnac1 α与相关蛋白DRASIC和/或BNaC2/ASIC形成异聚体。最近，我们还发现了一种假定的支架蛋白（PICK1），它与bnal α结合，存在于触摸终端中，因此可能是触觉机械转导复合体的附加成分。我们现在需要知道bnac1 α和PICK1是否可能参与本体感觉末端器官（如肌纺锤体）和高频太平洋小体的机械感觉。我们将用抗bnac1 α和PICK1的抗体进行测试。我们需要了解bnac1 α（可能还有PICK1）从DRG细胞体到外周的定向运输，这是DRG中蛋白质分选的一种新模式。我们将用标记bna1alpha的病毒转染DRG，并改变其细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，我们需要鉴定触觉转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来实现(1)结合bnac1 α， DRASIC或BNaC2/ASIC，或(2)与触觉所需的其他线虫蛋白同源。这些研究将有助于阐明触觉、本体感觉和某些疼痛形式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.