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.

The central nervous system (CNS) is one of the most complex physiological systems, and treatment of CNS disorders represents an area of major medical need. One critical aspect of the CNS is its lack of regeneration, such that damage is often permanent. The damage often leads to neurodegeneration, and so strategies for neuroprotection could lead to major medical advances. The G protein-coupled receptor (GPCR) family is one of the major receptor classes, and they have been successfully targeted clinically. One class of GPCRs is those activated by bioactive lysophospholipids as ligands, especially sphingosine-1-phosphate (S1P) and lysophosphatidic acid (LPA). Research has been increasingly demonstrating the important roles that S1P and LPA, and their receptors, play in physiology and disease. In this review, I describe the role of S1P and LPA receptors in neurodegeneration and potential roles in neuroprotection. Much of our understanding of the role of S1P receptors has been through pharmacological tools. One such tool, fingolimod (also known as FTY720), which is a S1P receptor agonist but a functional antagonist in the immune system, is clinically efficacious in multiple sclerosis by producing a lymphopenia to reduce autoimmune attacks; however, there is evidence that fingolimod is also neuroprotective. Furthermore, fingolimod is neuroprotective in many other neuropathologies, including stroke, Parkinson’s disease, Huntington’s disease, Rett syndrome, Alzheimer’s disease, and others that are discussed here. LPA receptors also appear to be involved, being upregulated in a variety of neuropathologies. Antagonists or mutations of LPA receptors, especially LPA₁, are neuroprotective in a variety of conditions, including cortical development, traumatic brain injury, spinal cord injury, stroke and others discussed here. Finally, LPA receptors may interact with other receptors, including a functional interaction with plasticity related genes.