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Increase, intracellular calcium leads to Disruption, neurotransmitter release
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 Do not cite|
Life Stage Applicability
Key Event Relationship Description
While intracellular Ca regulation is an important aspect of a number of processes in a variety of cells, it is particularly critical in nerve cell terminals where Ca mediates transmitter release (Augustine et al., 1987). Many synaptic connections during brain development involve calcium signaling, which directs structural as well as functional adaptation in neurons (Lohmann 2009; Michaelson and Lohmann 2010) and astrocytes (Navarette et al., 2013) to establish synaptic selectivity in the developing brain (Katherine von Stackelberg 2015). While astrocytes have long been known to support neuronal signaling, there is increasing evidence that astrocytes detect synaptic activity and engage in reciprocal signaling with neurons, again based on variations in intracellular Ca2+ (Volterra et al., 2014; Barkera and Ullian 2008).
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 AOP "Activation of MEK-ERK1/2 leads to deficits in learning and cognition via disrupted neurotransmitter release", 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
Lead (1-30 uM) was also observed to induce a concentration-dependent release of dopamine from striatal synaptosomes under conditions of spontaneous release (Minnema et al., 1986). Similar lead induced neurotransmitter release has been demonstrated for acetylcholine at the neuromuscular junction, as reflected by increase miniature-end-plate potentials (Cooper and Manalis 1983), and in cortical synaptosomes (Suszkiw et al., 1984). Although the mechanisms by which lead induces transmitter release are unresolved, the increased release may result from an increase in intrasynaptosomal free calcium which has been shown to increase release (Katz 1969).
Uncertainties and Inconsistencies
Synaptotagmin I (Syt) is a Ca2+ -sensing protein found in neurotransmitter vesicles and is responsible for promoting vesicular fusion in the presence of Ca2+ signaling (Chicka et al., 2008). Pb2+ bound Syt with 1000-fold higher affinity than Ca2+, which may prevent detection of Ca2+ signaling essential to neurotransmission (Bouton et al., 2001). Although Pb2+ exposure did not affect Syt protein expression in cultured hippocampal neurons (Neal et al., 2010), it is possible that Pb2+ may interfere with the Ca2+-sensing ability of Syt in neurons, thus masking the cellular signal for Ca2+-dependent vesicular release (Neal and Guilarte 2010).
Pb2+ interactions with Syt may be related to the ability of Pb2+ to mimic Ca2+ (Neal and Guilarte 2010). Pb2+ has an ionic radius of 1.2 Å, which is similar to the ionic radius of Ca2+ (0.99 Å) (Chao et al., 1984; Garza et al., 2006). The positive charges and high electronegativity (2.33 on the Pauling scale) of Pb2+ may allow it to interact with the same residues on Ca2+ binding sites that interact with Ca2+ ions (Garza et al., 2006). Pb2+ has been shown to interact with several neuronal intracellular Ca2+-binding proteins in addition to Syt (described above), such as the Ca2+-binding protein calmodulin (CaM) (Chao et al., 1984; Habermann et al., 1983; Kern et al., 2000), the CaM/Ca2+-dependent phosphatase calcineurin (Kern and Audesirk 2000), CaMKII (Toscano et al., 2005), and protein kinase C (Simons 1993; Sun et al., 1999; Toscano and Schanne 2000; Long et al., 1994), suggesting that Ca2+ mimicry may be a common characteristic of Pb2+ toxicity (Bressler et al., 1999; Marchetti 2003; Richardt et al., 1986). Thus, the ability of Pb2+ to mimic Ca2+ may interfere with normal synaptic signaling events (Neal and Guilarte 2010).
Another hypothesis regarding the disruption of neurotransmission is that Pb2+ may interfere with Ca2+ signals by inhibiting Ca2+ channels (Xiao et al., 2006; Braga et al., 1999; 35). Neurotransmission relies on the influx of Ca2+ from P/Q-, N-, and to some extent R-type voltage-gated Ca2+ channels (VGCCs) (Xu et al., 2007). Pb2+ has been shown to inhibit VGCCs in recombinant systems with high affinity (Peng et al., 2002). Furthermore, removal of extracellular Ca2+ resulted in identical effects on IPSC frequency as Pb2+ exposure, suggesting that the Pb2+-induced inhibition of IPSC frequency is via reduction of Ca2+ influx through VGCCs (Xiao et al., 2006). Inhibition of presynaptic VGCCs may prevent the necessary rise in internal Ca2+ required for fast, Ca2+-dependent vesicular release, thus interfering with neurotransmission (Neal and Guilarte 2010).
Cadmium may block the influx of Ca2+ through membrane channels into the nerve terminal following the action potential, these decrease in calcium influx caused by Cd would be associated with an altered transmitter release (Antonio et al., 1999).
Known modulating factors
Calcium efflux and induced spontaneous transmitter release occur on a seconds to minutes time-scale (Minnema et al., 1988).
Known Feedforward/Feedback loops influencing this KER
It has been clear for quite some time that influx of calcium at the synapse mediates synaptic plasticity in adult as well as developing neurons (Malenka et al., 1988). Despite this long-standing appreciation of the importance of calcium signaling for synaptic plasticity, it is virtually unknown what the properties of calcium transients are that determine whether a synapse becomes potentiated or depressed (Malenka and Bear 2004). Some models suggest that moderate increases in calcium may activate primarily phosphatases (e.g., calcineurin and protein phosphatase-1) that in turn facilitate synaptic depression (Mansuy and Shenolikar 2006). In contrast, the activation of kinases (e.g., calcium/calmodulin-dependent protein kinase II, CaMKII) by high-amplitude calcium transients may favor potentiation (Lisman et al., 2002). This is in fact an interesting parallel to the regulation of attractive vs. repulsive axon guidance by calcium: larger calcium transients can activate CaMKII and induce turns toward the side of calcium elevation, whereas smaller calcium increases activate the phosphatases calcineurin and phosphatase-1 and trigger repulsive turns (Wen et al., 2004; Zheng and Poo 2007).
Domain of Applicability
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