Physiological Roles of Non-Neuronal NMDA Receptors

Glutamate serves as the dominant central nervous system (CNS) excitatory neurotransmitter, in part by activating N-methyl-D-aspartate receptors (NMDARs). While the structure, function, and distribution of neuronal NMDARs have been extensively elucidated, NMDARs are also expressed across a wide spectrum of non-neuronal cells, including central and peripheral glial cells, endothelium, kidney, bone, pancreas, and others. These receptors are poorly understood compared to neuronal receptors, but there is a developing consensus that they have distinct structural and functional properties when activated by glutamate, NMDAR co-agonists, and in some cases by metabolites of tryptophan and methionine. It is also clear that non-neuronal NMDARs may participate in an array of physiological and pathophysiological processes, including but not limited to bone deposition, wound healing, insulin secretion, blood-brain barrier integrity, and myelination. These developing lines of evidence are stimulating exploration of non-neuronal NMDARs as a therapeutic target in several disorders.