Astrocyte ERK phosphorylation precedes K(+)-induced swelling but follows hypotonicity-induced swelling.
Hypotonicity following water intoxication and/or salt loss leads to mainly astrocytic brain swelling. Astrocytic swelling also occurs following brain trauma or ischemia, together with an increase in extracellular K(+) ([K(+)](o)), stimulating a bumetanide/furosemide/ethacrynic acid-inhibitable cotransporter, NKCC1, that accumulates Na(+) and K(+) together with 2 Cl(-) and osmotically obliged water. Either type of swelling may become fatal and is associated with phosphorylation of extracellular regulated kinases 1 and 2 (ERK(1/2)). Only the swelling associated with elevated [K(+)](o), leads to an increase in astrocytic proliferation and in expression of the astrocytic marker, glial fibrillary acidic protein. These differences prompted us to investigate key aspects of the molecular pathways between hypotonicity-induced and high-K(+)-mediated swelling in primary cultures of mouse astrocytes. In the latter Ca(2+)-mediated, AG1478-inhibitable transactivation of the epidermal growth factor (EGF) receptor leads, via bumetanide-inhibitable activation of the mitogen activated protein (MAP) kinase pathway to ERK phosphorylation and to NKCC1-mediated swelling. In the former, inhibition of the MAP kinase pathway, but not of EGF receptor activation, abolishes ERK phosphorylation, but has no effect on swelling, indicating that activation of ERK is a result, not a cause, of the swelling.
Department of Clinical Pharmacology, China Medical University, Shenyang, China.
Liping
L
Cai
Ting
T
Du
Dan
D
Song
Baoman
B
Li
Leif
L
Hertz
Liang
L
Peng
D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism; D000072198:ADAM17 Protein; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D001929:Brain Edema / Q000378:metabolism* / Q000473:pathology; D002034:Bumetanide / Q000494:pharmacology; D002455:Cell Division / Q000502:physiology; D002478:Cells, Cultured; D002614:Chelating Agents / Q000494:pharmacology; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D066246:ErbB Receptors / Q000378:metabolism; D066257:Heparin-binding EGF-like Growth Factor; D007038:Hypotonic Solutions / Q000494:pharmacology; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D048728:MAP Kinase Kinase Kinase 1 / Q000037:antagonists & inhibitors; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D010766:Phosphorylation / Q000502:physiology; D011188:Potassium / Q000494:pharmacology; D034741:RNA, Small Interfering; D049994:Sodium Potassium Chloride Symporter Inhibitors / Q000494:pharmacology; D014869:Water Intoxication / Q000378:metabolism* / Q000473:pathology; D019061:src-Family Kinases / Q000037:antagonists & inhibitors
D002614:Chelating Agents; C587884:Hbegf protein, mouse; D066257:Heparin-binding EGF-like Growth Factor; D007038:Hypotonic Solutions; D036341:Intercellular Signaling Peptides and Proteins; D034741:RNA, Small Interfering; D049994:Sodium Potassium Chloride Symporter Inhibitors; D002034:Bumetanide; C070379:1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid acetoxymethyl ester; D004533:Egtazic Acid; D066246:ErbB Receptors; D019061:src-Family Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048728:MAP Kinase Kinase Kinase 1; D051722:ADAM Proteins; D000072198:ADAM17 Protein; D011188:Potassium