Acute stress induces visceral hypersensitivity via glucocorticoid receptor-mediated membrane insertion of TRPM8: Involvement of a non-receptor tyrosine kinase Pyk2

被引:7
作者
Luo, Qing-Qing [1 ]
Wang, Bo [1 ]
Chen, Xin [1 ]
Qiu, Hong-Yi [1 ]
Li, Wen-Ting [1 ]
Yan, Xiu-Juan [1 ]
Chen, Sheng-Liang [1 ]
机构
[1] Shanghai Jiao Tong Univ, Key Lab Gastroenterol & Hepatol, Div Gastroenterol & Hepatol, Minist Hlth,Renji Hosp,Sch Med,Shanghai Inst Dige, 145 Middle Shandong Rd, Shanghai 200001, Peoples R China
基金
中国国家自然科学基金;
关键词
irritable bowel syndrome; psychological stress; Pyk2; transient receptor potential channels; visceral pain; IRRITABLE-BOWEL-SYNDROME; PSYCHOLOGICAL STRESS; GROWTH-FACTOR; RAT MODEL; TRPV1; PHOSPHORYLATION; SENSITIZATION; HYPERALGESIA; INFLAMMATION; ACTIVATION;
D O I
10.1111/nmo.13877
中图分类号
R57 [消化系及腹部疾病];
学科分类号
摘要
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.
引用
收藏
页码:1514 / 1528
页数:15
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