The role of intracellular sodium (Na+) in the regulation of calcium (Ca2+)-mediated signaling and toxicity

Abstract

It is known that activated N-methyl-D-aspartate receptors (NMDARs) are a major route of excessive calcium ion (Ca(2+)) entry in central neurons, which may activate degradative processes and thereby cause cell death. Therefore, NMDARs are now recognized to play a key role in the development of many diseases associated with injuries to the central nervous system (CNS). However, it remains a mystery how NMDAR activity is recruited in the cellular processes leading to excitotoxicity and how NMDAR activity can be controlled at a physiological level. The sodium ion (Na(+)) is the major cation in extracellular space. With its entry into the cell, Na(+) can act as a critical intracellular second messenger that regulates many cellular functions. Recent data have shown that intracellular Na(+) can be an important signaling factor underlying the up-regulation of NMDARs. While Ca(2+) influx during the activation of NMDARs down-regulates NMDAR activity, Na(+) influx provides an essential positive feedback mechanism to overcome Ca(2+)-induced inhibition and thereby potentiate both NMDAR activity and inward Ca(2+) flow. Extensive investigations have been conducted to clarify mechanisms underlying Ca(2+)-mediated signaling. This review focuses on the roles of Na(+) in the regulation of Ca(2+)-mediated NMDAR signaling and toxicity.

P2X7 receptor activation downmodulates Na+-dependent high-affinity GABA and glutamate transport into rat brain cortex synaptosomes

“…Moreover, when Na + -entry through the P2X7 receptor pore was selectively blocked with calmidazolium the effect of BzATP on GABA and glutamate uptake was prevented, thus giving a strong indication that BzATP effects were mainly (if not exclusively) mediated by lowering the Na + -coupled transporter driving-force. Hence, our results point toward a novel mechanism implicated in the decrease of GABA and glutamate uptake by synaptic nerve terminals, which might depend on the decline of the Na + driving-force necessary for amino-acid transportation across the plasma membrane operated by P2X7 receptor activation (Wonnemann et al, 2000;Richerson and Wu, 2003;Kanner, 2006;Lo et al, 2008;Yu et al, 2010). A similar dependence on transmembrane Na + -gradient was also observed for the glutamate uptake by the RBA-2 astrocytic cell line (Lo et al, 2008).…”

“…Brain activity is accompanied by significant Na + -influx from the extracellular space, through a variety of paths including permeation via ligand-gated cation channels, like P2X purinoceptors (Lo et al, 2008;Yu et al, 2010). Activation of the P2X7 receptor results in intense Na + -influx that may alter the Na + equilibrium and lead to GABA and glutamate uptake downmodulation by lowering the transport driving-force.…”

Nmda Receptor Internalization Down-Regulates Nmda Receptor-Mediated Synaptic Responses Through the Inhibition of Remaining (Non-Internalized) Surface Nmda Receptors

“…N-methyl-D-aspartate receptors (NMDARs) are a subtype of glutamate receptors and involved in many physiological and pathophysiological processes, such as synaptic plasticity, learning and memory, neuronal development and death [6,7,8,9,10,11] . Neuronal surface NMDARs are known to undergo homologous and heterologous internalization, which can be induced respectively by stimulating both the glutamate and glycine binding sites on the receptor [12,13] and by stimulating group 1 metabotropic glutamate receptors (mGluRs) [14,15,16,17,18] .…”

“…Our previous studies have shown that through intracellular signaling mediated by Na + and/or Ca 2+ neuronal surface NMDARs may cross talk to each other and therefore the activity of one NMDAR can be regulated by other NMDARs [11,23,24] . Based on these findings, we questioned: may endocytosis of some NMDARs affect the activity of remaining (non-internalized) neuronal surface NMDARs?…”

The neuroprotective effect of a hydroalcoholic extract of Piper aduncum “matico” in an in vitro model of neurodegeneration

“…De los resultados se observa que neuronas tratadas con el agonista sintético NMDA resultan en un aumento significativo en la intensidad de fluorescencia para los niveles de calcio intracelular. Esto concuerda respecto a estudios que indican que iones Ca 2+ entran a las neuronas a través de varias vías en los que R-NMDA activados constituyen una de las mayores rutas del excesivo influjo, lo cual a su vez puede conllevar a cambios en la plasticidad sináptica (Yu et al 2010). Sin embargo, éstos valores disminuyen significativamente (sin llegar al nivel basal) cuando las neuronas son tratadas con NMDA más P. aduncum, lo cual Figura 5.…”