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.