Glutamate signaling in benign and malignant disorders: current status, future perspectives, and therapeutic implications

Stacey S Willard, Shahriar Koochekpour, Stacey S Willard, Shahriar Koochekpour

Abstract

Glutamate, a nonessential amino acid, is the major excitatory neurotransmitter in the central nervous system. As such, glutamate has been shown to play a role in not only neural processes, such as learning and memory, but also in bioenergetics, biosynthetic and metabolic oncogenic pathways. Glutamate has been the target of intense investigation for its involvement not only in the pathogenesis of benign neurodegenerative diseases (NDDs) such as Parkinson's disease, Alzheimer's disease, schizophrenia, multiple sclerosis, and amyotropic lateral sclerosis (ALS), but also in carcinogenesis and progression of malignant diseases. In addition to its intracellular activities, glutamate in secreted form is a phylogenetically conserved cell signaling molecule. Glutamate binding activates multiple major receptor families including the metabotropic glutamate receptors (mGluRs) and ionotropic glutamate receptors (iGluRs), both of which have been implicated in various signaling pathways in cancer. Inhibition of extracellular glutamate release or glutamate receptor activation via competitive or non-competitive antagonists decreases growth, migration and invasion and induces apoptosis in breast cancer, melanoma, glioma and prostate cancer cells. In this review, we discuss the current state of glutamate signaling research as it relates to benign and malignant diseases. In addition, we provide a synopsis of clinical trials using glutamate antagonists for the treatment of NDD and malignant diseases. We conclude that in addition to its potential role as a metabolic biomarker, glutamate receptors and glutamate-initiated signaling pathways may provide novel therapeutic opportunities for cancer.

Keywords: GRM1a; Glutamate; brain; breast; cancer; glioma.; iGluR; mGluR; mGluR1a; melanoma; prostate; signaling.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interest exists.

Figures

Fig 1
Fig 1
iGluR activation. This figure illustrates the activation and opening of iGluR ion channels. In Panel A, the closed channel does not allow ion influx. Upon Glu binding (Panel B), conformational change in iGluR subunits allows Ca2+ influx to occur by diffusion through the open channel.
Fig 2
Fig 2
mGluR activation. This figure depicts the mGluR1a receptor before (Panel A) and after (Panel B) Glu binding. Relevant domains are noted, such as: amino terminal domain (ATD), cysteine-rich domain (CRD), transmembrane domain (TMD), cytoplasmic tail domain (CTD). Binding of Glu activates G-protein signaling and downstream second messenger pathways including PKC, PLC and Ca2+ signaling.
Fig 3
Fig 3
GluR involvement in different cancer types. This Venn diagram illustrates the similarities and differences among the four cancer types with respect to the involvement of glutamatergic signaling. Glioma, breast cancer, prostate cancer and melanoma are represented by the circles. Overlapping areas indicate the expressional and functional similarities for GluR genes among different cancer types investigated. For example, mGluR proteins have been detected in all four cancer types, therefore this phrase is in an area where all four circles overlap.

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Source: PubMed

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