Activation of MEK, ERK1/2 leads to Increase, intracellular calcium

Astrocytes are networked together by a series of gap junctions permitting to propagate Ca²⁺ waves through the linked network (Lobsiger and Cleveland 2007), and Ca2+-mediated intercellular communication is a mechanism by which astrocytes communicate with each other and modulate the activity of adjacent cells (Verderio et al., 2001). Metal mixture (MM) induced alteration in astrocyte morphology may influence [Ca²⁺]i (Barres et al., 1989); in contrast, an increase in [Ca²⁺]_i may also play a key role in altering astrocyte cytoskeleton, affecting the glia-neuron interaction (Shelton et al., 2000).

Inhibition of GFAP immunoreactivity by MM in developing brain appears to be caused by astrocyte apoptosis. In primary cultures of astrocytes, our data show that MM synergistically induced apoptosis (Rai and others 2010). This was manifested by the activation of MEK/ERK, followed by the activation of JNK pathways, which then enhanced intracellular Ca2+ levels and subsequently ROS generation.

This KER was identified as part of an Environmental Protection Agency effort to represent putative AOPs from peer-reviewed literature which were heretofore unrepresented in the AOP-Wiki. The KER is referenced in publications which were cited in the originating work for the putative AOPs "Activation of MEK-ERK1/2 leads to deficits in learning and cognition via disrupted neurotransmitter release" and "Activation of MEK-ERK1/2 leads to deficits in learning and cognition via ROS and apoptosis", Katherine von Stackelberg & Elizabeth Guzy & Tian Chu & Birgit Claus Henn, 2015. Exposure to Mixtures of Metals and Neurodevelopmental Outcomes: A Multidisciplinary Review Using an Adverse Outcome Pathway Framework, Risk Analysis, John Wiley & Sons, vol. 35(6), pages 971-1016, June.