Center of Excellence for Stress and Mental Health, Veterans Affairs Hospital, La Jolla, CA, USA.
Psychopharmacology (Berl). 2013 Oct;229(4):579-89. doi: 10.1007/s00213-013-3114-9. Epub 2013 May 31.
Hypersignaling of corticotropin releasing factor (CRF) has been implicated in stress disorders; however, many of its downstream mechanisms of action remain unclear. In vitro, CRF1 receptor activation initiates multiple cell signaling cascades, including protein kinase A (PKA), protein kinase C (PKC), and mitogen-activated protein kinase kinase MEK1/2 signaling. It is unclear, however, which of these signaling cascades mediate CRF-induced behaviors during stress.
We examined the role of PKA, PKC, and MEK1/2 signaling pathways in CRF-induced anxiety as measured by startle hyperreactivity.
Mice treated with intracerbroventricular (ICV) ovine CRF (oCRF) were pretreated with the PKA inhibitor Rp-cAMPS, PKC inhibitor bisindolylmaleimide (BIM), or MEK1/2 inhibitor PD98059 (ICV) and assessed for acoustic startle reactivity.
The PKC inhibitor BIM significantly attenuated CRF-induced increases in startle. BIM was also able to block startle increases induced by oCRF when both compounds were infused directly into the bed nucleus of stria terminalis (BNST). PKA and MEK1/2 inhibition had no significant effects on CRF-induced changes in startle at the dose ranges tested. CRF-induced disruption of prepulse inhibition was not significantly reversed by any of the three pretreatments at the dose ranges tested.
PKC signaling is required for CRF-induced increases in startle, and this effect is mediated at least in part at the BNST. These findings suggest that PKC signaling cascades (1) may be important for the acute effects of CRF to induce startle hyperreactivity and (2) support further research of the role of PKC signaling in startle abnormalities relevant to disorders such as posttraumatic stress disorder.
促肾上腺皮质释放因子（CRF）的过度信号传递与应激障碍有关；然而，其许多下游作用机制仍不清楚。体外研究表明，CRF1 受体的激活会引发多种细胞信号级联反应，包括蛋白激酶 A（PKA）、蛋白激酶 C（PKC）和丝裂原活化蛋白激酶激酶 MEK1/2 信号通路。然而，尚不清楚这些信号通路中的哪一种介导了 CRF 在应激状态下引起的行为。
我们研究了 PKA、PKC 和 MEK1/2 信号通路在 CRF 诱导的焦虑中的作用，这种焦虑通过惊跳反应过度来衡量。
用脑室内（ICV）注射绵羊 CRF（oCRF）处理的小鼠，用 PKA 抑制剂 Rp-cAMPS、PKC 抑制剂双吲哚马来酰亚胺（BIM）或 MEK1/2 抑制剂 PD98059（ICV）预处理，并评估其对声惊跳反应的影响。
PKC 抑制剂 BIM 显著减弱了 CRF 引起的惊跳反应增加。当两种化合物直接注入终纹床核（BNST）时，BIM 也能阻断 oCRF 引起的惊跳反应增加。在测试的剂量范围内，PKA 和 MEK1/2 抑制对 CRF 引起的惊跳反应变化没有显著影响。在测试的剂量范围内，三种预处理均不能显著逆转 CRF 引起的条件性抑制反应的破坏。
PKC 信号通路是 CRF 引起惊跳反应增加所必需的，这种作用至少部分是在 BNST 中介导的。这些发现表明，PKC 信号级联反应（1）可能对 CRF 引起的惊跳反应过度的急性效应很重要，（2）支持进一步研究 PKC 信号在与创伤后应激障碍等障碍相关的惊跳反应异常中的作用。
