Glucocorticoid receptor and mitogen-activated protein kinase activity after restraint stress and acoustic trauma.
Restraint stress (RS) protects auditory function against acoustic trauma by activating glucocorticoid receptors (GR) in the cochlea. In a search for the signaling pathways downstream to GR that may be involved in RS-induced protection we report here (1) a downregulation of phosphorylated extracellular signal-regulated kinases 1 and 2 (pERK 1/2) after the combined treatment of RS and acoustic trauma; (2) activation of phospho-p38 in the auditory nerve after RS; (3) the abolition of these two effects by pretreatment with metyrapone (an inhibitor of corticosterone synthesis) and RU486 (a GR antagonist); and (4) no activation of c-jun-N-terminal kinases 1 and 2 (JNK 1/2), ERK, or p38 after acoustic trauma alone. Thus we demonstrate a GR-dependent ERK-mediated pathway that modulates auditory function after RS and acoustic trauma. These findings reveal new mechanisms that underlie hearing loss and will have implications for the development of pharmacological strategies for protecting against acoustic trauma.
Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
Inna
I
Meltser
Yeasmin
Y
Tahera
Barbara
B
Canlon
D000818:Animals; D003051:Cochlea / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D003056:Cochlear Nerve / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D003345:Corticosterone / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D006317:Hearing Loss, Noise-Induced / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D006727:Hormone Antagonists / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D008297:Male; D051379:Mice; D008808:Mice, Inbred CBA; D015735:Mifepristone / Q000494:pharmacology; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D011965:Receptors, Glucocorticoid / Q000187:drug effects / Q000378:metabolism*; D012149:Restraint, Physical / Q000009:adverse effects*; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000378:metabolism; D013136:Spiral Ganglion / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D013315:Stress, Psychological / Q000378:metabolism* / Q000503:physiopathology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D006727:Hormone Antagonists; D011725:Pyridines; D011965:Receptors, Glucocorticoid; C013109:metapyrone; D015735:Mifepristone; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases; D003345:Corticosterone