Acute stress induces visceral hypersensitivity via glucocorticoid receptor-mediated membrane insertion of TRPM8: Involvement of a non-receptor tyrosine kinase Pyk2
Acute stress induces visceral hypersensitivity via glucocorticoid receptor-mediated membrane insertion of TRPM8: Involvement of a non-receptor tyrosine kinase Pyk2
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DOI：
10.1111/nmo.13877
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发表时间：
2020-05-11
影响因子：
3.5
通讯作者：
Chen, Sheng-Liang
中科院分区：
文献类型：
--
作者：
Luo, Qing-Qing;Wang, Bo;Chen, Sheng-Liang
背景心理应激是肠易激综合征（IBS）发生和复发的重要因素。应激诱导的内脏高敏感性（VH）是IBS的一个重要病理生理学组成部分，其机制尚不完全清楚。我们的目的是测试是否瞬时受体电位melastatin 8（TRPM 8）参与急性应激诱导的VH。方法大鼠进行1小时的水回避应激（WAS）。内脏敏感性用内脏对结直肠扩张的反应来测量。结果WAS诱导的VH依赖于糖皮质激素受体（GR）和TRPM 8通道。在背根神经节（DRG）衍生的细胞系中，皮质酮迅速（30分钟内）诱导TRPM 8的膜表达。这种作用被GR拮抗作用抑制，并被膜不可渗透的皮质酮模仿。GR下游的PKA、PI 3 K/Akt和PKC通路共同促进TRPM 8的膜表达，参与了WAS诱导的VH。非受体酪氨酸激酶Pyk 2可能作为PKA、PI 3 K/Akt和PKC通路的汇聚点，通过酪氨酸磷酸化TRPM 8促进TRPM 8在L 6-S2背根神经节的膜插入，并参与WAS诱导的VH。从机制上讲，Pyk 2可以作为协调多种蛋白激酶信号传导并触发TRPM 8磷酸化和膜插入的关键介质。
Background Psychological stress is an important factor for the development and recurrence of irritable bowel syndrome (IBS). The mechanisms underlying stress-induced visceral hypersensitivity (VH), a key pathophysiological component in IBS, are still incompletely understood. We aimed to test whether transient receptor potential melastatin 8 (TRPM8) participates in acute stress-induced VH.Methods Rats were subjected to 1-hour water avoidance stress (WAS). Visceral sensitivity was measured with visceromotor response to colorectal distension. Western blot and immunofluorescence were applied to evaluate the expression of GR and TRPM8 and activation of PKA, Akt, and PKC pathways.Results WAS-caused VH depended on glucocorticoid receptors (GRs) and TRPM8 channels. In a dorsal root ganglion (DRG)-derived cell line, corticosterone rapidly (within 30 minutes) induced membrane expression of TRPM8. This effect was inhibited by GR antagonism and was mimicked by membrane-impermeable corticosterone. PKA, PI3K/Akt, and PKC pathways, which lied downstream of GR and acted in parallel to promote membrane expression of TRPM8, contributed to WAS-induced VH. The non-receptor tyrosine kinase Pyk2, which may serve as a convergence point for PKA, PI3K/Akt, and PKC pathways, facilitated membrane insertion of TRPM8 via tyrosine-phosphorylating TRPM8 in L6-S2 DRGs and participated in WAS-induced VH.Conclusions Collectively, acute stress-induced VH could involve membrane-bound GR-dependent enhancement of TRPM8 function in nociceptive DRG neurons. Mechanistically, Pyk2 could act as a key mediator that coordinates multiple protein kinase signaling and triggers phosphorylation and membrane insertion of TRPM8.