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Activation of MEK, ERK1/2 leads to Increase, intracellular calcium
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding||Point of Contact||Author Status||OECD Status|
|Activation of MEK-ERK1/2 leads to deficits in learning and cognition via disrupted neurotransmitter release||adjacent||Not Specified||Not Specified||Travis Karschnik (send email)||Under development: Not open for comment. Do not cite|
|Activation of MEK-ERK1/2 leads to deficits in learning and cognition via ROS and apoptosis||adjacent||Not Specified||Not Specified||Travis Karschnik (send email)||Under development: Not open for comment. Do not cite|
Life Stage Applicability
|Birth to < 1 month||Moderate|
|1 to < 3 months||Moderate|
Key Event Relationship Description
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.
Evidence Collection Strategy
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.
Evidence Supporting this KER
Uncertainties and Inconsistencies
Known modulating factors
Exposures were conducted for 2 min, 5 min, 10 min, 30 min, 1 h, 2 h, and 24 h. The [Ca2+]i release reached its peak after 30 min of MM treatment (Rai and others 2010).
Known Feedforward/Feedback loops influencing this KER
The activity of many protein kinases is modulated by Ca2+ and/or Ca2+/calmodulin either directly (PKC, CaM kinase II) or indirectly (PKA via stimulation of adenylyl cyclase and phosphodiesterase by Ca2+/calmodulin) (Kern et al., 1995). Therefore, the effects of Ca2+ and protein kinases on cytoskeletal proteins and neurite initiation are likely to be mediated, at least in part, by changes in protein phosphorylation (Kern et al., 1995).
Domain of Applicability
Asit Rai and others, Characterization of Developmental Neurotoxicity of As, Cd, and Pb Mixture: Synergistic Action of Metal Mixture in Glial and Neuronal Functions, Toxicological Sciences, Volume 118, Issue 2, December 2010, Pages 586–601, https://doi.org/10.1093/toxsci/kfq266
Barres, B. A., L. L. Chun, and Corey. "Calcium current in cortical astrocytes: induction by cAMP and neurotransmitters and permissive effect of serum factors." Journal of Neuroscience 9.9 (1989): 3169-3175.
Jaldety, Yael, and Haim Breitbart. "ERK1/2 mediates sperm acrosome reaction through elevation of intracellular calcium concentration." Zygote 23.5 (2015): 652-661.
Kern, Marcey, and Gerald Audesirk. "Inorganic lead may inhibit neurite development in cultured rat hippocampal neurons through hyperphosphorylation." Toxicology and applied pharmacology 134.1 (1995): 111-123.
Levin, Jacqueline B., and Laura N. Borodinsky. "Injury-induced Erk1/2 signaling tissue-specifically interacts with Ca2+ activity and is necessary for regeneration of spinal cord and skeletal muscle." Cell calcium 102 (2022): 102540.
Lobsiger, C. S., and Cleveland, D. W. (2007). Glial cells as intrinsic components of non-cell-autonomous neurodegenerative disease. Nat. Neuro-sci. 10, 1355–1360.
Shelton, Marilee K., and Ken D. McCarthy. "Hippocampal astrocytes exhibit Ca2+‐elevating muscarinic cholinergic and histaminergic receptors in situ." Journal of neurochemistry 74.2 (2000): 555-563.
Verderio, Claudia, and Michela Matteoli. "ATP mediates calcium signaling between astrocytes and microglial cells: modulation by IFN-γ." The Journal of Immunology 166.10 (2001): 6383-6391.