Glial Na⁺‐dependent ion transporters in pathophysiological conditions

Abstract

Sodium dynamics are essential for regulating functional processes in glial cells. Indeed, glial Na+ signaling influences and regulates important glial activities, and plays a role in neuron-glia interaction under physiological conditions or in response to injury of the central nervous system (CNS). Emerging studies indicate that Na+ pumps and Na+-dependent ion transporters in astrocytes, microglia, and oligodendrocytes regulate Na+ homeostasis and play a fundamental role in modulating glial activities in neurological diseases. In this review, we first briefly introduced the emerging roles of each glial cell type in the pathophysiology of cerebral ischemia, Alzheimer’s disease, epilepsy, Parkinson’s disease, Amyotrophic Lateral Sclerosis, and myelin diseases. Then, we discussed the current knowledge on the main roles played by the different glial Na+-dependent ion transporters, including Na+/K+ ATPase, Na+/Ca2+ exchangers, Na+/H+ exchangers, Na+-K+-Cl− cotransporters, and Na+-HCO3− cotransporter in the pathophysiology of the diverse CNS diseases. We highlighted their contributions in cell survival, synaptic pathology, gliotransmission, pH homeostasis, and their role in glial activation, migration, gliosis, inflammation, and tissue repair processes. Therefore, this review summarizes the foundation work for targeting Na+-dependent ion transporters in glia as a novel strategy to control important glial activities associated with Na+ dynamics in different neurological disorders.

Crosslink between calcium and sodium signalling

“…This makes NCX instrumental for shaping Ca 2+ and Na + signalling and thus affecting the excitation-contraction coupling, neurotransmitters transport, mitochondrial bioenergetics and neuron-glia interactions among many other (Bers, 2002; Kirischuk et al , 2012; De Stefani et al , 2016; Parpura et al , 2016; Robinson & Jackson, 2016). On the other hand, small anomalies in allosteric regulation of NCX or coupled ion-transport systems may end-up with devastating outcomes (Wagner et al , 2015; Boscia et al , 2016). For example, Na + -driven uptake of neurotransmitters (e.g., GABA or glutamate) elevates [Na + ] i , thus promoting Ca 2+ entry through NCX operating in the reverse mode and increase [Ca 2+ ] i with ensuing excitotoxicity (Kirischuk et al , 1997; Boscia et al , 2016; Rose & Verkhratsky, 2016).…”

“…On the other hand, small anomalies in allosteric regulation of NCX or coupled ion-transport systems may end-up with devastating outcomes (Wagner et al , 2015; Boscia et al , 2016). For example, Na + -driven uptake of neurotransmitters (e.g., GABA or glutamate) elevates [Na + ] i , thus promoting Ca 2+ entry through NCX operating in the reverse mode and increase [Ca 2+ ] i with ensuing excitotoxicity (Kirischuk et al , 1997; Boscia et al , 2016; Rose & Verkhratsky, 2016). Moreover, when E NCX and E m are close, any small changes in the extracellular [K + ] (for example released from neurones during repolarisation) may change membrane potential thus affecting the rates and directionality of NCX.…”

Selective role of Na+/H+ exchanger in Cx3cr1+ microglial activation, white matter demyelination, and post‐stroke function recovery

“…NHE1 plays an important role in regulating microglial intracellular pH (pH i ) homeostasis, their activation, and migration (Boscia et al, 2016; Liu et al, 2010; Shi et al, 2013; Zhao et al, 2016; Zhu et al, 2016). In particular, NHE1 maintains optimal pH i to support NADPH oxidase (NOX) function during microglial activation (Lam et al, 2013).…”

D‐Aspartate treatment attenuates myelin damage and stimulates myelin repair

“…Another interesting finding of our study is that D-Asp exposure significantly and dose-dependently upregulated the transcripts levels of the Na + /Ca 2+ exchanger NCX3, a plasma membrane component of myelin membranes (Gopalakrishnan et al, 2013) whose increased expression and activity has been shown to be essential for controlling [Na + ] i and [Ca 2+ ] i in OPC during differentiation and myelin synthesis (Boscia et al, 2012(Boscia et al, , 2016aFriess et al, 2016). Consistent with the boosting effects of D-Asp on OPC development through a mechanisms involving the activation of both glutamate receptors and NCX3 exchangers, we found that the upregulation of NCX3 transcripts following D-Asp exposure was significantly prevented by the NMDA receptor blocker and the pharmacological blockade of NCX3 exchanger significantly prevented myelin marker increase after D-Asp exposure.…”

“…In this regard, glutamate signaling through a-amino-3hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA) and N-Methyl-D-Aspartate (NMDA) receptors has garnered the main interest as inductive signal prompting OPC to differentiate and remyelinate (Yuan et al, 1998;Li et al, 2013;Fannon et al, 2015;Gautier et al, 2015). In line, mounting evidence suggests that the activation of Ca 2+ -dependent pathways through glutamate receptors or the Na + /Ca 2+ exchanger NCX3 may influence oligodendrocyte maturation, myelin synthesis, and remyelination processes (Boscia et al, 2012(Boscia et al, , 2016aMartinez-Lozada et al, 2014;Casamassa et al, 2016;Friess et al, 2016).…”