Astrocyte ERK phosphorylation precedes K+-induced swelling but follows hypotonicity-induced swelling

Abstract

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.

Dependence of Corneal Epithelial Cell Proliferation on Modulation of Interactions Between ERK1/2 and NKCC1

“…2: left panel) that EGF induced transient increases in apparent cell volume, which were associated with ERK1/2-induced NKCC1 phosphorylation. This cause and effect relationship is in agreement with a study using mice astrocytes in which exposure to a high K + containing medium induced swelling that is dependent on ERK1/2 activation of NKCC1 [34]. The changes induced by PKC activation are also supportive of this cause and effect relationship.…”

“…6). This dependence of MAPK activation on Ca 2+ influx induced by EGF was described in conjunctival goblet cells and mice astrocytes [36,34].…”

Role of Glycogenolysis in Stimulation of ATP Release from Cultured Mouse Astrocytes by Transmitters and High K+ Concentrations

“…Abrogation of K + -stimulated release of ATP by inhibition of glycogenolysis could have been expected, since the L-channel-mediated pathway opened by the addition of 45 mM K + (Cai et al, 2011) is inhibited when glycogenolysis is prevented (Xu et al, 2013). L-channel function is also known to be dependent on energy metabolism (Kostyuk, 1984).…”

Ammonia-induced Na,K-ATPase/ouabain-mediated EGF receptor transactivation, MAPK/ERK and PI3K/AKT signaling and ROS formation cause astrocyte swelling

“…We now have shown that also AKT need to be activated upstream of ERK, but where this occurs in relation to Ras and Raf is not known with certainty. We have also previously shown that ERK phosphorylation can lead to NKCC1 activation, but not determined the intermediate steps (Cai et al, 2011). The swelling caused by 3 mM ammonia is delayed, beginning after 12 h, a delay caused by the requirement for ROS and its action on NKCC1.…”