Increase, intracellular calcium leads to Disruption, neurotransmitter release

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).

Calcium efflux and induced spontaneous transmitter release occur on a seconds to minutes time-scale (Minnema et al., 1988).

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).