Functional coupling of TRPM2 and extrasynaptic NMDARs exacerbates excitotoxicity in ischemic brain injury

Protein kinase C‐mediated phosphorylation of transient receptor potential melastatin type 2 Thr738 counteracts the effect of cytosolic Ca2+ and elevates the temperature threshold

“…Importantly, PKC-mediated phosphorylation of TRPM2 appears to counteract the effect of cytosolic Ca 2+ on TRPM2 thresholds, and may function as negative feedback signalling following cytosolic Ca 2+ elevation caused by TRPM2 activation. The recent finding that the N-terminus of TRPM2 physically interacts with PKCγ to modify NMDA receptor functions (Zong et al, 2022) further supports our findings.…”

Excitatory Synaptic Transmission in Ischemic Stroke: A New Outlet for Classical Neuroprotective Strategies

“…Among them, the connection of TRPM2 and TRPM4 channels with the extrasynaptic NMDAR is especially obvious after cerebral ischemia, which leads to the enhancement of excitotoxicity and the aggravation of neuronal death [ 173 , 174 ]. It is reasonable to speculate that this may be the unique function of a protein family, that is, specifically migrating the NMDAR to the outer surface of the synapse after forming a complex with the NMDAR.…”

“…It is reasonable to speculate that this may be the unique function of a protein family, that is, specifically migrating the NMDAR to the outer surface of the synapse after forming a complex with the NMDAR. Therefore, the inhibitors that destroy the interface of this kind of complex, such as TAT-EE3, C8, and C19, can correspondingly target the esNMDAR, which will show powerful new effects and broad prospects in neuroprotection [ 173 , 174 ].…”

NMDA Receptor C-Terminal Domain Signalling in Development, Maturity, and Disease

“…Since proteomic data from mouse and human cortex and hippocampus indicates that TRPM4 is absent at the synapse, this study proposes that NMDAR-TRPM4 interactions may offer some explanation as to the differences in the response of synaptic vs. extrasynaptic NMDARs during increased Ca 2+ load. Similarly, it has also been observed that TRPM2 ion channels functionally couple with extrasynaptic NMDARs to enhance excitotoxicity in mouse models of ischaemic brain injury [ 99 ]. Trpm2 knock-out (KO) mice exhibited a reduced infarct volume and an improved neurological performance compared to WT mice following middle cerebral artery occlusion (MCAO), which is in agreement with observations made previously in these KOs [ 100 ].…”

“…Trpm2 knock-out (KO) mice exhibited a reduced infarct volume and an improved neurological performance compared to WT mice following middle cerebral artery occlusion (MCAO), which is in agreement with observations made previously in these KOs [ 100 ]. Furthermore, it was found that Protein kinase C gamma (PKCγ) was readily coimmunoprecipitated with anti-TRPM2 in brain lysates and that this interaction was increased following MCAO [ 99 ]. Considering that PKCγ has been shown to regulate NMDAR surface trafficking [ 101 , 102 ], this study suggests that TRPM2-NMDAR interactions may exacerbate excitotoxicity by increasing the surface expression of extrasynaptic NMDARs, enhancing extrasynaptic NMDAR activity thereby promoting cell death.…”