Coupling diverse routes of calcium entry to mitochondrial dysfunction and glutamate excitotoxicity Export

@article{citeulike:5781482, abstract = {10.1073/pnas.0903546106 Overactivation of NMDA receptors (NMDARs) is a critical early step in glutamate-evoked excitotoxic injury of CNS neurons. Distinct NMDAR-coupled pathways specified by, for example, receptor location or subunit composition seem to govern glutamate-induced excitotoxic death, but there is much uncertainty concerning the underlying mechanisms of pathway selection. Here we ask whether, and if so how, route-specific vulnerability is coupled to Ca overload and mitochondrial dysfunction, which is also a known, central component of exitotoxic injury. In cultured hippocampal neurons, overactivation of only extrasynaptic NMDARs resulted in Ca entry strong enough to promote Ca overload, which subsequently leads to mitochondrial dysfunction and cell death. Receptor composition per se appears not to be a primary factor for specifying signal coupling, as NR2B inhibition abolished Ca loading and was protective only in predominantly NR2B-expressing young neurons. In older neurons expressing comparable levels of NR2A- and NR2B-containing NMDARs, amelioration of Ca overload required the inhibition of extrasynaptic receptors containing both NR2 subunits. Prosurvival synaptic stimuli also evoked Ca entry through both N2A- and NR2B-containing NMDARs, but, in contrast to excitotoxic activation of extrasynaptic NMDARs, produced only low-amplitude cytoplasmic Ca spikes and modest, nondamaging mitochondrial Ca accumulation. The results\^{a}€”showing that the various routes of excitotoxic Ca entry converge on a common pathway involving Ca overload-induced mitochondrial dysfunction\^{a}€”reconcile and unify many aspects of the \^{a}€œroute-specific\^{a}€ and \^{a}€œcalcium load-dependent\^{a}€ views of exitotoxic injury.}, author = {Stanika, Ruslan I. and Pivovarova, Natalia B. and Brantner, Christine A. and Watts, Charlotte A. and Winters, Christine A. and Andrews, S. Brian}, citeulike-article-id = {5781482}, citeulike-linkout-0 = {http://dx.doi.org/10.1073/pnas.0903546106}, citeulike-linkout-1 = {http://www.pnas.org/content/106/24/9854.abstract}, citeulike-linkout-2 = {http://www.pnas.org/content/106/24/9854.full.pdf}, citeulike-linkout-3 = {http://view.ncbi.nlm.nih.gov/pubmed/19482936}, citeulike-linkout-4 = {http://www.hubmed.org/display.cgi?uids=19482936}, day = {16}, doi = {10.1073/pnas.0903546106}, journal = {Proceedings of the National Academy of Sciences}, keywords = {calcium, mitochondria, nmda}, month = {June}, number = {24}, pages = {9854--9859}, posted-at = {2009-09-14 15:44:04}, priority = {2}, title = {Coupling diverse routes of calcium entry to mitochondrial dysfunction and glutamate excitotoxicity}, url = {http://dx.doi.org/10.1073/pnas.0903546106}, volume = {106}, year = {2009} }

TY - JOUR ID - citeulike:5781482 L3 - citeulike-article-id:5781482 N2 - 10.1073/pnas.0903546106 Overactivation of NMDA receptors (NMDARs) is a critical early step in glutamate-evoked excitotoxic injury of CNS neurons. Distinct NMDAR-coupled pathways specified by, for example, receptor location or subunit composition seem to govern glutamate-induced excitotoxic death, but there is much uncertainty concerning the underlying mechanisms of pathway selection. Here we ask whether, and if so how, route-specific vulnerability is coupled to Ca overload and mitochondrial dysfunction, which is also a known, central component of exitotoxic injury. In cultured hippocampal neurons, overactivation of only extrasynaptic NMDARs resulted in Ca entry strong enough to promote Ca overload, which subsequently leads to mitochondrial dysfunction and cell death. Receptor composition per se appears not to be a primary factor for specifying signal coupling, as NR2B inhibition abolished Ca loading and was protective only in predominantly NR2B-expressing young neurons. In older neurons expressing comparable levels of NR2A- and NR2B-containing NMDARs, amelioration of Ca overload required the inhibition of extrasynaptic receptors containing both NR2 subunits. Prosurvival synaptic stimuli also evoked Ca entry through both N2A- and NR2B-containing NMDARs, but, in contrast to excitotoxic activation of extrasynaptic NMDARs, produced only low-amplitude cytoplasmic Ca spikes and modest, nondamaging mitochondrial Ca accumulation. The results—showing that the various routes of excitotoxic Ca entry converge on a common pathway involving Ca overload-induced mitochondrial dysfunction—reconcile and unify many aspects of the “route-specific” and “calcium load-dependent” views of exitotoxic injury. IS - 24 JF - Proceedings of the National Academy of Sciences EP - 9859 TI - Coupling diverse routes of calcium entry to mitochondrial dysfunction and glutamate excitotoxicity VL - 106 SP - 9854 KW - calcium KW - mitochondria KW - nmda AU - Stanika, Ruslan AU - Pivovarova, Natalia AU - Brantner, Christine AU - Watts, Charlotte AU - Winters, Christine AU - Andrews, Brian PY - 2009/06/16/ UR - http://dx.doi.org/10.1073/pnas.0903546106 ER -