Metal Toxicity at the Synapse: Presynaptic, Postsynaptic, and Long-Term Effects

Figure 5

Proteins involved in the formation of long-term potentiation (LTP) and toxic effects of metals. LTP consists of different forms: early-phase LTP (E-LTP), which lasts only a few hours, and late-phase LTP (L-LTP), which lasts for several days. E-LTP includes short-term potentiation (STP), which is dependent on NMDA receptor activation and Ca²⁺/calmodulin and LTP-1 that involves protein kinase C (PKC) and Ca²⁺/calmodulin-dependent protein kinase- (CaMK-) dependent phosphorylation. While STP can be formed by activation of NMDA and calmodulin dependent enzymes, LTP-1 requires activation of PKC via DAG that is produced after the activation of mGluRs. PKC and CaMKII then phosphorylate AMPA and NMDA receptors. L-LTP consists of the later phases of LTP, which are LTP-2 and LTP-3. LTP-2 requires synthesis of new proteins and receptors whereas LTP3 requires gene transcription. Activation of adenylate cyclase and cAMP-dependent activation of PKA are required for the formation of the later phases of LTP. LTP-3 depends on the activation of extracellular signal- related kinase 1/2 (ERK1/2) and CaM kinase IV, which in turn phosphorylate CREB and lead to new protein synthesis. Other factors such as p38 mitogen-activated protein kinase (p38 MAPK) leads to the formation of long-term depression (LTD). Several of the molecules required to produce these different forms of LTP have been identified and are targets for metal toxicity, which have been shown (red arrows indicate inhibition whereas green arrows indicate activation by metals. Black arrows indicate activation that occurs during normal formation of LTP).