Modulation of NMDAR Subunit Expression by TRPM2 Channels Regulates Neuronal Vulnerability to Ischemic Cell Death
Open Access
- 30 October 2013
- journal article
- Published by Society for Neuroscience in Journal of Neuroscience
- Vol. 33 (44), 17264-17277
- https://doi.org/10.1523/jneurosci.1729-13.2013
Abstract
Neuronal vulnerability to ischemia is dependent on the balance between prosurvival and prodeath cellular signaling. In the latter, it is increasingly appreciated that toxic Ca2+influx can occur not only via postsynaptic glutamate receptors, but also through other cation conductances. One such conductance, the Transient receptor potential melastatin type-2 (TRPM2) channel, is a nonspecific cation channel having homology to TRPM7, a conductance reported to play a key role in anoxic neuronal death. The role of TRPM2 conductances in ischemic Ca2+influx has been difficult to study because of the lack of specific modulators. Here we used TRPM2-null mice (TRPM2−/−) to study how TRPM2 may modulate neuronal vulnerability to ischemia. TRPM2−/−mice subjected to transient middle cerebral artery occlusion exhibited smaller infarcts when compared with wild-type animals, suggesting that the absence of TRPM2 is neuroprotective. Surprisingly, field potentials (fEPSPs) recorded during redox modulation in brain slices taken from TRPM2−/−mice revealed increased excitability, a phenomenon normally associated with ischemic vulnerability, whereas wild-type fEPSPs were unaffected. The upregulation in fEPSP in TRPM2−/−neurons was blocked selectively by a GluN2A antagonist. This increase in excitability of TRPM2−/−fEPSPs during redox modulation depended on the upregulation and downregulation of GluN2A- and GluN2B-containing NMDARs, respectively, and on augmented prosurvival signaling via Akt and ERK pathways culminating in the inhibition of the proapoptotic factor GSK3β. Our results suggest that TRPM2 plays a role in downregulating prosurvival signals in central neurons and that TRPM2 channels may comprise a therapeutic target for preventing ischemic damage.Keywords
This publication has 64 references indexed in Scilit:
- Dependence of NMDA/GSK-3β Mediated Metaplasticity on TRPM2 Channels at Hippocampal CA3-CA1 SynapsesMolecular Brain, 2011
- Sex Differences in Neuroprotection Provided by Inhibition of TRPM2 Channels following Experimental StrokeJournal of Cerebral Blood Flow & Metabolism, 2011
- Synaptic versus extrasynaptic NMDA receptor signalling: implications for neurodegenerative disordersNature Reviews Neuroscience, 2010
- Activation of NR2A Receptors Induces Ischemic Tolerance through CREB SignalingJournal of Cerebral Blood Flow & Metabolism, 2010
- Coupling diverse routes of calcium entry to mitochondrial dysfunction and glutamate excitotoxicityProceedings of the National Academy of Sciences of the United States of America, 2009
- TRPM2 Functions as a Lysosomal Ca 2+ -Release Channel in β CellsScience Signaling, 2009
- Ca2+‐dependent induction of TRPM2 currents in hippocampal neuronsJournal Of Physiology-London, 2009
- Oxidative impairment of hippocampal long‐term potentiation involves activation of protein phosphatase 2A and is prevented by ketone bodiesJournal of Neuroscience Research, 2008
- TRPM2-mediated Ca2+ influx induces chemokine production in monocytes that aggravates inflammatory neutrophil infiltrationNature Medicine, 2008
- Pro-survival signalling from the NMDA receptorBiochemical Society Transactions, 2006