Department of Cell Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
Cell Rep. 2012 Sep 27;2(3):511-7. doi: 10.1016/j.celrep.2012.07.014. Epub 2012 Aug 23.
Heightened nociceptor function caused by inflammatory mediators such as bradykinin (BK) contributes to increased pain sensitivity (hyperalgesia) to noxious mechanical and thermal stimuli. Although it is known that sensitization of the heat transducer TRPV1 largely subserves thermal hyperalgesia, the cellular mechanisms underlying mechanical hyperalgesia have been elusive. The role of the mechanically activated (MA) channel piezo2 (known as FAM38B) present in mammalian sensory neurons is unknown. We test the hypothesis that piezo2 activity is enhanced by BK, an algogenic peptide that induces mechanical hyperalgesia within minutes. Piezo2 current amplitude is increased and inactivation is slowed by bradykinin receptor beta 2 (BDKRB2) activation in heterologous expression systems. Protein kinase A (PKA) and protein kinase C (PKC) agonists enhance piezo2 activity. BDKRB2-mediated effects are abolished by PKA and PKC inhibitors. Finally, piezo2-dependent MA currents in a class of native sensory neurons are enhanced 8-fold by BK via PKA and PKC. Thus, piezo2 sensitization may contribute to PKA- and PKC-mediated mechanical hyperalgesia.
升高的伤害感受器功能由炎症介质如缓激肽（BK）引起，导致对有害的机械和热刺激的疼痛敏感性增加（痛觉过敏）。尽管已知热传感器 TRPV1 的敏化在很大程度上导致了热痛觉过敏，但机械痛觉过敏的细胞机制仍难以捉摸。存在于哺乳动物感觉神经元中的机械激活（MA）通道 piezo2（称为 FAM38B）的作用尚不清楚。我们测试了以下假设：BK 可增强 piezo2 活性，BK 是一种在数分钟内引起机械性痛觉过敏的致痛肽。在异源表达系统中，缓激肽受体β 2（BDKRB2）的激活增加了 piezo2 电流幅度并减慢了失活速度。蛋白激酶 A（PKA）和蛋白激酶 C（PKC）激动剂增强了 piezo2 活性。PKA 和 PKC 抑制剂可消除 BDKRB2 介导的作用。最后，通过 PKA 和 PKC，BK 在一类天然感觉神经元中增强了依赖于 piezo2 的 MA 电流 8 倍。因此，piezo2 敏化可能有助于 PKA 和 PKC 介导的机械性痛觉过敏。
