ABSTRACT
Regulator of G-protein signaling protein (RGS)-2 is a modulator of anxiety and dysregulation of oxidative stress is implicated in anxiety. Also, RGS2 expression is reported to be induced by oxidative stress. Thus, if oxidative stress induces RGS2 expression and lack of RGS2 causes anxiety, then mechanisms that link RGS2 and oxidative stress potentially critical to anxiety must be revealed. Our study is the first to suggest role of RGS2 in regulation of enzymes involved in antioxidant defense namely glyoxalase-1 and glutathione reductase-1 via activation of p38 MAPK and PKC pathways in an Sp-1 dependent manner.
Subject(s)
Antioxidants/metabolism , Homeostasis , Neurons/metabolism , RGS Proteins/metabolism , Animals , Blotting, Western , Cell Line , Cell Survival/drug effects , DNA, Antisense/genetics , Enzyme Activation/drug effects , Gene Expression/drug effects , Glutathione Reductase/genetics , Glutathione Reductase/metabolism , Hydrogen Peroxide/pharmacology , Lactoylglutathione Lyase/genetics , Lactoylglutathione Lyase/metabolism , Mice , Neurons/cytology , Neurons/drug effects , Oxidants/pharmacology , Oxidative Stress/drug effects , Protein Carbonylation/drug effects , Protein Kinase C/metabolism , RGS Proteins/genetics , Reverse Transcriptase Polymerase Chain Reaction , Signal Transduction/drug effects , Superoxide Dismutase/genetics , Superoxide Dismutase/metabolism , p38 Mitogen-Activated Protein Kinases/metabolismABSTRACT
G-protein coupled receptor kinase 3 (GRK3) mediates desensitization of alpha(2)-adrenergic (alpha(2)-AR) and CRF(1) receptors. CRF(1) receptors, alpha(2)-AR and GRK3, are localized to the primary source of noradrenergic inputs to higher brain centers critical in both the response to stress and the development of depression, namely, locus coeruleus (LC). This study utilizing CATH.a cells (derived from the LC), demonstrates for the first time, that the stress hormone, CRF selectively up-regulates GRK3 expression via an ERK1/2-mediated mechanism accompanied by the activation of Sp-1 and Ap-2 transcription factors. This observation has important implications for the regulation of stress signaling in the brain.
