NMDA Receptor and Its Emerging Role in Cancer

Abstract

Glutamate is a key player in excitatory neurotransmission in the central nervous system (CNS). The N-methyl-D-aspartate receptor (NMDAR) is a glutamate-gated ion channel which presents several unique features and is involved in various physiological and pathological neuronal processes. Thanks to great efforts in neuroscience, its structure and the molecular mechanisms controlling its localization and functional regulation in neuronal cells are well known. The signaling mediated by NMDAR in neurons is very complex as it depends on its localization, composition, Ca²⁺ influx, and ion flow-independent conformational changes. Moreover, NMDA receptors are highly diffusive in the plasma membrane of neurons, where they form heterocomplexes with other membrane receptors and scaffold proteins which determine the receptor function and activation of downstream signaling. Interestingly, a recent paper demonstrates that NMDAR signaling is involved in epithelial cell competition, an evolutionary conserved cell fitness process influencing cancer initiation and progress. The idea that NMDAR signaling is limited to CNS has been challenged in the past two decades. A large body of evidence suggests that NMDAR is expressed in cancer cells outside the CNS and can respond to the autocrine/paracrine release of glutamate. In this review, we survey research on NMDAR signaling and regulation in neurons that can help illuminate its role in tumor biology. Finally, we will discuss existing data on the role of the glutamine/glutamate metabolism, the anticancer action of NMDAR antagonists in experimental models, NMDAR synaptic signaling in tumors, and clinical evidence in human cancer.

Keywords: NMDAR; cancers; glutamate; metabolism; neuron.

Figure 1

NMDA receptor structure. NMDAR is a heterotetrametric transmembrane receptor constituted by two obligatory NMDAR1 subunits and a further two NMDAR2 or NMDAR3 subunits. NMDAR subunits are characterized by an extracellular amino-terminal domain (ATD), an extracellular ligand-binding domain (LBD), four transmembrane domains (TMD), and an intracellular C-terminal domain (CTD). Ca²⁺: calcium; Gly: glycine; Glu: glutamate; Mg²⁺: magnesium.

Figure 2

NMDA receptor ionotropic and non-ionotropic pathways in neurons. NMDAR is localized either at the synaptic or extrasynaptic compartments exerting opposite functions. Synaptic NMDARs are involved in pro-survival functions, whereas extrasynaptic NMDARs promote a specific cell death called excitotoxicity. In the ionotropic pathway, once activated, NMDA channels allow the entrance of Ca²⁺, which triggers downstream intracellular signaling. In the non-ionotropic pathway, ion flow-independent conformational changes of NMDAR stimulate nNOS/p38MAPK pathway and/or AP2 endocytosis. Ca²⁺: calcium; CaM: calmodulin.

Figure 3

NMDA receptor interactome. NMDAR forms heterocomplexes with other proteins which determine receptor function and activated downstream signaling. Dark red line: direct NMDAR interactions; light red lines: indirect NMDAR interactions. DR: dopamine receptor; EGFR: epidermal growth factor receptor; EphB2R: ephrin receptor; GKAP: guanylate kinase-associated protein; mGluR: metabotropic glutamate receptor; nAchR: nicotinic acetylcholine receptors; PTK: protein-tyrosine kinase; µOR: opioid receptor.

Figure 4

Glutamine and glutamate metabolic fates. Cancer cells rewire their metabolism to sustain fast growth and adapt to oxidative stress. Glutamine entrance and metabolism are enhanced to support new biosynthesis of essential molecules, such as amino acids, nucleotides, and fatty acids, to fuel TCA cycle for energy and to control oxidative stress through glutathione synthesis. aKG: alpha-ketoglutarate; GLS: glutaminase; GLUD: glutamate dehydrogenase; IDH: isocitrate dehydrogenase; IMM: inner mitochondrial membrane; ME1: malic enzyme; NEAA: non-essential amino acids; OAA: oxaloacetic acid; OMM: outer mitochondrial membrane; TCA cycle: tricarboxylic acid cycle; xCT: glutamate-cystine antiporter.

Figure 5

Summary graph of genomic alterations of GRIN2A gene and their distribution in cancer studies from AACR Project GENIE available in the cBioPortal.

Figure 6

Summary graph of genomic alterations of GRIN2A and GRIN2B genes and their distribution in cancer studies from TCGA pan-cancer Project available in the cBioPortal.