Possible roles of heteroreceptor complexes in excitotoxic processes

Abstract

Excitotoxicity represents a neuropathological process, describing the toxic actions of excitatory neurotransmitters, where the excessive or prolonged activation of glutamate receptors triggers a cascade of events leading to neuronal injury or death. Under conditions of reduced energy availability and increased oxidative stress neurons become particularly vulnerable to excitotoxicity and a large body of available evidence indicates that excitotoxicity represents a central mechanism in the pathogenesis of acute and degenerative diseases of the central nervous system. Astrocytes represent key elements in the regulation of glutamate homeostasis by their opposing functions of glutamate uptake and release, and microglial cells play an important role in the response to damage. Depending on the phenotype they assume when activated, microglial cells can trigger immune defense or neuroprotective processes. To perform their functions both glial cell populations monitor the extracellular space through a panel of receptors. Furthermore, a variety of signaling pathways also contribute to the modulation of the glutamatergic transmission, acting on specific cell receptors expressed by neurons, astrocytes, and microglia. In the last decades, evidence has been provided that receptors of almost all families can establish structural receptor-receptor interactions, leading to the formation of heteroreceptor complexes at the cell membrane of neurons and glial cells. The cooperativity that emerges in the actions of ligands of the monomers forming these assemblies provides the cell decoding apparatus with flexible dynamics in terms of recognition and signal transduction and allows an integration of the incoming signals already at the membrane level. Available data on possible modulatory roles played by heteroreceptor complexes in excitotoxic processes will be here reviewed and discussed. From the pharmacological standpoint, these findings may offer possibilities to explore novel therapeutic strategies targeting receptor complexes to address disorders of the central nervous system associated with dysregulation of glutamatergic signaling.

Keywords

• receptor-receptor interactions
• receptor complexes
• astrocytes
• microglia
• glutamate
• excitotoxicity