Distinct Influx Pathways, Not Calcium Load, Determine Neuronal Vulnerability to Calcium Neurotoxicity

Abstract

Many forms of neurodegeneration are ascribed to excessive cellular Ca 2~loading (Ca2~hypothesis). We examined quantitatively whether factors other than 1Ca 2l oading were determinants of excitotoxic neurode~'eneration. Cell survival, morphology, free intracellular Cas1 concentration ([Ca2~]), and 45Ca2~accumulation were measured in cultured cortical neurons loaded with known quantities of Ca2through distinct transmembrane pathways triggered by excitatory amino acids, cell membrane depolarization, or Ca2ĩonophores. Contrary to the Ca2h ypothesis, the relationships between Ca2~load and cell survival, free [Ca2~]~, and Ca2~-inducedmorphological alterations depended primarily on the route of Ca2~influx, not the Ca2~load. Notably, Ca2~loading via NMDA receptor channels was toxic, whereas identical Ca2~loads incurred through voltage-sensitive Ca2~channels were completely innocuous. Furthermore, accounting quantitatively for Ca2~loading via NMDA receptors uncovered a previously unreported component of L-glutamate neurotoxicity apparently not mediated by ionotropic or metabotropic glutamate receptors. lt was synergistic with toxicity attributable to glutamate-evoked Ca2~loading, and correlated with enhanced cellular ATP depletion. This previously unrecognized toxic action of glutamate constituted a chief excitotoxic mechanism under conditions producing submaximal Ca2~loading. We conclude that (a) Ca2~neurotoxicity is a function of the Ca2~infltlx pathway, not Ca2 load, and (b) glutamate toxicity may not be restricted to its actions on glutamate receptors.

Changes in calcium dynamics following the reversal of the sodium-calcium exchanger have a key role in AMPA receptor-mediated neurodegeneration via calpain activation in hippocampal neurons

“…This observation is in agreement with previous studies by other groups, showing that the VSCC pathway of Ca 2 þ entry is not particularly toxic to cells 34 or involved in calpain activation. 35 Ca 2 þ entering the cell by specific entry points is more efficient in triggering cell death than other pathways -source-specificity hypothesis.…”

Bidirectional Regulation of Neuronal Nitric-oxide Synthase Phosphorylation at Serine 847 by the N-Methyl-d-aspartate Receptor

“…Several studies have examined the increase in intracellular free Ca 2ϩ in cultured neurons under varying conditions of excitatory stimulation (10,11,56,61,62). The magnitude of the increase of Ca 2ϩ correlated with the increase in the concentration of glutamate (56).…”

“…Exposure of NMDARs to elevated levels of glutamate is the primary cause of neuronal death after traumatic injuries, including stroke, seizures, and mechanical trauma (51,52). Stimulation of cultured neurons with 100 M glutamate and to higher glutamate concentrations mimics these pathological effects (14,25,(53)(54)(55)(56). A pathological dose of glutamate, 100 M, induced the dephosphorylation of nNOS at Ser 847 (Fig.…”

Synapses, NMDA receptor activity and neuronal Aβ production in Alzheimer’s disease

“…This theory was supported by experimental studies showing alterations in calcium signaling both in sporadic and in familial cases of AD (Mattson , 2004 ;Smith et al , 2005 ;Stutzmann , 2005 ). Comparatively to other routes of Ca 2 + entry in neuronal cells, N -methyl-d -aspartate receptors (NMDARs), a subtype of ionotropic glutamate receptors, are of particular interest because of their special ability to gate high levels of Ca 2 + infl ux (Choi et al , 1988 ;Sattler et al , 1998 ). These receptors have been extensively studied for their crucial role in synaptic plasticity and excitotoxicity (Rothman and Olney , 1995 ;Waxman and Lynch , 2005 ).…”