RATIONALE: 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. OBJECTIVES: We examined the role of PKA, PKC, and MEK1/2 signaling pathways in CRF-induced anxiety as measured by startle hyperreactivity. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
RATIONALE: 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. OBJECTIVES: We examined the role of PKA, PKC, and MEK1/2 signaling pathways in CRF-induced anxiety as measured by startle hyperreactivity. METHODS: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. RESULTS: 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. CONCLUSIONS: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.
Authors: Michal Bajo; Maureen T Cruz; George R Siggins; Robert Messing; Marisa Roberto Journal: Proc Natl Acad Sci U S A Date: 2008-06-09 Impact factor: 11.205
Authors: M Beyermann; N Heinrich; K Fechner; J Furkert; W Zhang; O Kraetke; M Bienert; H Berger Journal: Br J Pharmacol Date: 2007-05-29 Impact factor: 8.739
Authors: Avis Brennan Hains; Mai Anh T Vu; Paul K Maciejewski; Christopher H van Dyck; Melissa Gottron; Amy F T Arnsten Journal: Proc Natl Acad Sci U S A Date: 2009-09-11 Impact factor: 11.205