Main path and byways: non‐vesicular glutamate release by system x_c⁻ as an important modifier of glutamatergic neurotransmission

Abstract

System xc− is a cystine/glutamate antiporter that exchanges extracellular cystine for intracellular glutamate. Cystine is intracellularly reduced to cysteine, a building block of GSH. As such, system xc− can regulate the antioxidant capacity of cells. Moreover, in several brain regions, system xc− is the major source of extracellular glutamate. As such this antiporter is able to fulfill key physiological functions in the CNS, while evidence indicates it also plays a role in certain brain pathologies. Since the transcription of xCT, the specific subunit of system xc−, is enhanced by the presence of reactive oxygen species and inflammatory cytokines, system xc− could be involved in toxic extracellular glutamate release in neurological disorders that are associated with increased oxidative stress and neuroinflammation. System xc− has also been reported to contribute to the invasiveness of brain tumors and, as a source of extracellular glutamate, could participate in the induction of peritumoral seizures. Two independent reviews (Lewerenz et al. 2013, Bridges et al. 2012), approached from a different perspective, have recently been published on the functions of system xc− in the central nervous system. In this review, we highlight novel achievements and insights covering the regulation of system xc− as well as its involvement in emotional behavior, cognition, addiction, neurological disorders and glioblastomas, acquired in the past few years.

Interleukin 1β Regulation of the System xc− Substrate-specific Subunit, xCT, in Primary Mouse Astrocytes Involves the RNA-binding Protein HuR

“…However, evidence also indicates that under particular circumstances, Sx c Ϫ can contribute to certain brain pathologies (for comprehensive review see Refs. [52][53][54]. The cytokine IL-1␤ also produces dichotomous results within the CNS (reviewed in Ref.…”

Inflammation, Glutamate, and Glia: A Trio of Trouble in Mood Disorders

“…LPSinduced activation of TLR3 and 4 increases surface expression of the xC-system and thus co-administration of LPS and the xC-system stimulator cystine can potentially lead to enhanced glutamate toxicity (Kigerl et al, 2012). Increases in xC-system function have been implicated in multiple medical disorders (Massie et al, 2015), but more intriguingly is being actively targeted for new drug development for the treatment of substance dependence (Baker et al, 2003).…”

Astrocytic transporters in Alzheimer's disease

“…System xc-also mediates glutamate release from astrocytes ( Figure 3). The non-vesicular (calcium-independent) glutamate release from astrocytes via system xc-is sufficient to activate neuronal glutamate receptors in the CNS and therefore system xc-directly contributes to neuronal excitability and synaptic plasticity (184,188,189).…”

“…Together these proteins mediate the heteroexchange of cystine and glutamate with a stoichiometry of cystine:glutamate of 1:1 at the plasma membrane. The complex can operate in either direction, but is generally considered to import cystine and export glutamate from the cell (183,184).…”