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.

TrendsGlutamate serves as the primary excitatory CNS neurotransmitter by activating a range of neuronal receptors, including NMDARs.Neuronal (n)NMDARs are extensively characterized. However, at least 12 additional cell types express NMDARs in neural and non-neural tissues. Awareness of these receptors has lagged behind nNMDARs but important trends are developing.Non-neuronal NMDARs are regulated by endogenous agonists, glutamate, quinolinic acid, and L-homocysteic acid.Glial cells express NMDARs with properties distinct from most neuronal cousins. Emerging data suggest that these receptors may be responsible for diverse physiological roles, including myelination, pain sensitivity, and inflammation.NMDARs in bone, kidney, pancreas, and other tissues are burgeoning therapeutic targets for disorders such as osteoporosis, acute renal injury, diabetes, and cancer.