A new villain in neuronal death

doi:10.1126/science.abe2791

GSTDTAP > 气候变化

DOI	10.1126/science.abe2791
	A new villain in neuronal death
	Susan Jones
	2020-10-09
发表期刊	Science
出版年	2020
英文摘要	Excitotoxicity is the process by which the excitatory amino acid neurotransmitter glutamate causes neuronal toxicity ([ 1 ][1]). A landmark study in 1987 revealed that Ca2+ influx into neurons through glutamate N -methyl-d-aspartate receptor channels (NMDARs) could trigger excitotoxicity ([ 2 ][2]), making Ca2+ ions potential villains as well as functionally critical signaling molecules in neurons. On page 191 of this issue, Yan et al. ([ 3 ][3]) reveal a newly discovered mechanism of NMDAR-mediated excitotoxicity: a physical interaction with TRPM4, a transient receptor potential channel ([ 4 ][4]). Small-molecule “interface inhibitors” prevent NMDAR-TRPM4 physical coupling and eliminate excitotoxicity in vitro and in vivo. This mechanism of excitotoxicity does not require NMDAR-mediated Ca2+ influx: TRPM4 is the new villain. Consequently, excitotoxicity can be halted without disrupting physiologically crucial NMDAR-mediated Ca2+ signaling. This presents opportunities in the design of therapeutics for disorders involving excitotoxicity, including stroke, epilepsy, and neurodegeneration. Glutamate, released at excitatory synapses in the vertebrate brain, binds to NMDARs to induce Ca2+-dependent forms of synaptic plasticity ([ 5 ][5]) and survival-promoting intracellular signaling pathways involving CREB \[cyclic adenosine monophosphate (cAMP) response element–binding protein\] ([ 6 ][6]). Glutamate can also spill over beyond the synapse and activate neighboring synaptic and extrasynaptic NMDARs. Excessive NMDAR-mediated Ca2+ influx is a widely accepted explanation for excitotoxicity ([ 7 ][7], [ 8 ][8]). A hitherto unrelated ion channel, TRPM4, is activated by cytoplasmic Ca2+ and is permeable to monovalent cations Na+ and K+ (but not to Ca2+), mediating membrane depolarization ([ 9 ][9]). TRPM4 has previously been linked to neuronal death: In mice, inhibition of TRPM4 reduces neurodegeneration, and genetic deletion of Trpm4 protects against glutamate excitotoxicity ([ 10 ][10]). Yan et al. demonstrate a physical interaction between NMDARs and TRPM4 in hippocampal cell cultures and brain tissue from mice. NMDARs are typically composed of GluN1, GluN2, and sometimes GluN3 subunits ([ 11 ][11]). TRPM4 specifically interacts with GluN2A and GluN2B, but not GluN2C/D, GluN1, or GluN3. The site of NMDAR-TRPM4 interaction was narrowed down to a cytoplasmic region of TRPM4, which the authors call TwinF. They further identify a highly conserved isoleucine-rich cytoplasmic sequence in GluN2A and GluN2B to which TwinF binds; they name this I4. A TwinF peptide used to block NMDAR-TRPM4 interaction was neuroprotective in three assays of cell death: (i) NMDAR-evoked excitotoxicity of neuronal cultures, (ii) oxygen-glucose deprivation–evoked cell death in neuronal cultures, and (iii) a small but significant reduction in ischemic brain damage in vivo after middle cerebral artery occlusion (MCAO) in mice. Small-molecule inhibitors that target the precise NMDAR-TRPM4 interaction, called compounds 8 and 19, were identified. In the mouse MCAO model and in retinal degeneration induced by NMDA (the selective NMDAR agonist for which the receptor was named), intraperitoneal delivery of compound 8 offered neuroprotection—a small but significant reduction in infarct volume and cell loss, as well as reduction in NMDAR-TRPM4 interaction by as much as 38%. Thus, these small and simple molecules could potentially be delivered systemically to patients. Rapid delivery would be required in acute excitotoxic injury—for example, after stroke or epilepsy—whereas in chronic neurodegenerative diseases, possible contributions of excitotoxicity to disease progression ([ 8 ][8]) might be mitigated over a longer time course. The authors hypothesize that NMDAR-TRPM4 coupling triggers “CREB shutoff” (CREB dephosphorylation) ([ 6 ][6], [ 12 ][12]). TwinF and compounds 8 and 19 appear to “detoxify” NMDAR signaling by preventing CREB shutoff. In addition, TwinF reduces NMDAR-induced mitochondrial membrane dysfunction. By disrupting NMDAR-TRPM4 coupling, harmful signaling pathways are silenced while neuroprotective signaling pathways are spared (see the figure). The mechanism by which physical coupling of NMDAR-TRPM4 brings about such neuroprotective effects is not yet elucidated, but it does not appear to involve Ca2+ signaling. A surprising finding is that blocking the NMDAR-TRPM4 interaction with TwinF or small-molecule inhibitors has no effect on normal synaptic NMDAR channel function recorded in hippocampal CA1 pyramidal neurons in mouse brain slices. Nor is there any effect on NMDAR-mediated Ca2+ influx and signaling in vitro. TRPM4 channel activity is also unaffected by blocking NMDAR interaction. Conventional NMDAR antagonists typically impair cognitive function ([ 13 ][13]), most likely by blocking NMDAR-mediated synaptic transmission, Ca2+ influx, and plasticity ([ 5 ][5]). Being able to target excitotoxicity while having no detrimental effect on NMDAR ionic current flux or calcium permeability in vitro constitutes an important step. It remains to be confirmed that the small-molecule inhibitors have no detrimental effects in vivo. ![Figure][14] Disrupting glutamate receptor interactions Synaptic N -methyl-d-aspartate receptor channels (NMDARs), activated by glutamate release and coincident membrane depolarization, trigger neuroprotective signaling pathways involving phosphorylated cAMP-responsive element–binding protein (pCREB). Extrasynaptic NMDARs that are activated by synaptic glutamate spillover interact with transient receptor potential monovalent cation channel 4 (TRPM4), triggering excitotoxic cell death. Blocking NMDAR-TRPM4 binding with an N/T inhibitor eliminates neuronal death signaling and enables neuroprotective synaptic signaling. GRAPHIC: KELLIE HOLOSKI/ SCIENCE A physical coupling between TRPM4 and NMDARs in mediating excitotoxicity explains a conundrum in NMDAR research: why NMDARs located at synapses appear to mediate prosurvival signaling, whereas NMDARs located away from the synapse appear to prevent this and indeed trigger prodeath signaling pathways ([ 6 ][6], [ 8 ][8], [ 12 ][12], [ 14 ][15]). Previous explanations for this include the subcellular localization of different signaling molecules or different concentrations of Ca2+ influx at synaptic versus extrasynaptic sites. Because TRPM4 is absent from synapses, this suggests that NMDAR-TRPM4 complexes would only form extrasynaptically, offering a satisfying explanation for this puzzle. Considerable research effort has focused on the role of Ca2+ in NMDAR-mediated excitotoxicity. The study of Yan et al. introduces a new villain, TRPM4. This requires reevaluation of the role of NMDARs in neuronal death. It may redirect research efforts away from Ca2+ and toward physical interactions of NMDARs, and it could provide another argument against developing NMDAR antagonist and channel blocker therapies. It is unknown whether the NMDAR-TRPM4 interaction will prove to be the primary (or even exclusive) excitotoxicity mechanism in a broader range of neurons. For example, neurodegeneration in Huntington's and Parkinson's diseases affects the basal ganglia ([ 14 ][15]), whereas Yan et al. studied hippocampal neurons. There is evidence for acute and chronic excitotoxicity in human neurological disorders ([ 8 ][8]), and so it may be illuminating to screen postmortem human brains from patients with neurodegenerative diseases for NMDAR-TRPM4 interactions. If higher amounts of interaction are seen compared with healthy subjects, can small-molecule protein interaction inhibitors be designed to produce a sufficiently robust yet safe disruption? Another intriguing question is whether NMDAR-TRPM4 interaction is triggered under normal physiological conditions and plays an important functional role, or is instead purely a pathological response to injury. After more than 30 years of research, perhaps Ca2+ signaling will ultimately be shown to have little importance in excitotoxicity—to be a hero and not a villain in neuronal signaling. 1. [↵][16]1. J. W. Olney , Science 164, 719 (1969). [OpenUrl][17][Abstract/FREE Full Text][18] 2. [↵][19]1. D. W. Choi , J. Neurosci. 7, 369 (1987). [OpenUrl][20][Abstract/FREE Full Text][21] 3. [↵][22]1. J. Yan et al ., Science 370, eaay3302 (2020). [OpenUrl][23][CrossRef][24] 4. [↵][25]1. P. Launay et al ., Cell 109, 397 (2002). [OpenUrl][26][CrossRef][27][PubMed][28][Web of Science][29] 5. [↵][30]1. C. Lüscher, 2. R. C. Malenka , Cold Spring Harb. Perspect. Biol. 4, a005710 (2012). [OpenUrl][31][Abstract/FREE Full Text][32] 6. [↵][33]1. G. E. Hardingham, 2. H. Bading , Nat. Rev. Neurosci. 11, 682 (2010). [OpenUrl][34][CrossRef][35][PubMed][36][Web of Science][37] 7. [↵][38]1. M. Arundine, 2. M. Tymianski , Cell Calcium 34, 325 (2003). [OpenUrl][39][CrossRef][40][PubMed][41][Web of Science][42] 8. [↵][43]1. J. Lewerenz, 2. P. Maher , Front. Neurosci. 9, 469 (2015). [OpenUrl][44][CrossRef][45][PubMed][46] 9. [↵][47]1. S. Choi 1. R. Guinamard, 2. C. Simard, 3. L. Sallé , in Encyclopedia of Signaling Molecules, S. Choi, Ed. (Springer, 2016). 10. [↵][48]1. B. Schattling et al ., Nat. Med. 18, 1805 (2012). [OpenUrl][49][CrossRef][50][PubMed][51] 11. [↵][52]1. D. J. A. Wyllie, 2. M. R. Livesey, 3. G. E. Hardingham , Neuropharmacology 74, 4 (2013). [OpenUrl][53][CrossRef][54][PubMed][55] 12. [↵][56]1. G. E. Hardingham, 2. Y. Fukunaga, 3. H. Bading , Nat. Neurosci. 5, 405 (2002). [OpenUrl][57][CrossRef][58][PubMed][59][Web of Science][60] 13. [↵][61]1. S. A. Lipton , Nat. Rev. Drug Discov. 5, 160 (2006). [OpenUrl][62][CrossRef][63][PubMed][64][Web of Science][65] 14. [↵][66]1. M. P. Parsons, 2. L. A. Raymond , Neuron 82, 279 (2014). [OpenUrl][67][CrossRef][68][PubMed][69][Web of Science][70] [1]: #ref-1 [2]: #ref-2 [3]: #ref-3 [4]: #ref-4 [5]: #ref-5 [6]: #ref-6 [7]: #ref-7 [8]: #ref-8 [9]: #ref-9 [10]: #ref-10 [11]: #ref-11 [12]: #ref-12 [13]: #ref-13 [14]: pending:yes [15]: #ref-14 [16]: #xref-ref-1-1 "View reference 1 in text" [17]: {openurl}?query=rft.jtitle%253DScience%26rft.stitle%253DScience%26rft.aulast%253DOlney%26rft.auinit1%253DJ.%2BW.%26rft.volume%253D164%26rft.issue%253D3880%26rft.spage%253D719%26rft.epage%253D721%26rft.atitle%253DBrain%2BLesions%252C%2BObesity%252C%2Band%2BOther%2BDisturbances%2Bin%2BMice%2BTreated%2Bwith%2BMonosodium%2BGlutamate%26rft_id%253Dinfo%253Adoi%252F10.1126%252Fscience.164.3880.719%26rft_id%253Dinfo%253Apmid%252F5778021%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [18]: /lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6Mzoic2NpIjtzOjU6InJlc2lkIjtzOjEyOiIxNjQvMzg4MC83MTkiO3M6NDoiYXRvbSI7czoyMjoiL3NjaS8zNzAvNjUxMy8xNjguYXRvbSI7fXM6ODoiZnJhZ21lbnQiO3M6MDoiIjt9 [19]: #xref-ref-2-1 "View reference 2 in text" [20]: {openurl}?query=rft.jtitle%253DJournal%2Bof%2BNeuroscience%26rft.stitle%253DJ.%2BNeurosci.%26rft.aulast%253DChoi%26rft.auinit1%253DD.%26rft.volume%253D7%26rft.issue%253D2%26rft.spage%253D369%26rft.epage%253D379%26rft.atitle%253DIonic%2Bdependence%2Bof%2Bglutamate%2Bneurotoxicity%26rft_id%253Dinfo%253Adoi%252F10.1523%252FJNEUROSCI.07-02-00369.1987%26rft_id%253Dinfo%253Apmid%252F2880938%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [21]: /lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6Njoiam5ldXJvIjtzOjU6InJlc2lkIjtzOjc6IjcvMi8zNjkiO3M6NDoiYXRvbSI7czoyMjoiL3NjaS8zNzAvNjUxMy8xNjguYXRvbSI7fXM6ODoiZnJhZ21lbnQiO3M6MDoiIjt9 [22]: #xref-ref-3-1 "View reference 3 in text" [23]: {openurl}?query=rft.jtitle%253DScience%26rft.stitle%253DScience%26rft.aulast%253DYan%26rft.auinit1%253DJ.%26rft.volume%253D370%26rft.issue%253D6513%26rft.spage%253Deaay3302%26rft.epage%253Deaay3302%26rft.atitle%253DCoupling%2Bof%2BNMDA%2Breceptors%2Band%2BTRPM4%2Bguides%2Bdiscovery%2Bof%2Bunconventional%2Bneuroprotectants%26rft_id%253Dinfo%253Adoi%252F10.1126%252Fscience.aay3302%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [24]: /lookup/external-ref?access_num=10.1126/science.aay3302&link_type=DOI [25]: #xref-ref-4-1 "View reference 4 in text" [26]: {openurl}?query=rft.jtitle%253DCell%26rft.stitle%253DCell%26rft.aulast%253DLaunay%26rft.auinit1%253DP.%26rft.volume%253D109%26rft.issue%253D3%26rft.spage%253D397%26rft.epage%253D407%26rft.atitle%253DTRPM4%2Bis%2Ba%2BCa2%252B-activated%2Bnonselective%2Bcation%2Bchannel%2Bmediating%2Bcell%2Bmembrane%2Bdepolarization.%26rft_id%253Dinfo%253Adoi%252F10.1016%252FS0092-8674%252802%252900719-5%26rft_id%253Dinfo%253Apmid%252F12015988%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [27]: /lookup/external-ref?access_num=10.1016/S0092-8674(02)00719-5&link_type=DOI [28]: /lookup/external-ref?access_num=12015988&link_type=MED&atom=%2Fsci%2F370%2F6513%2F168.atom [29]: /lookup/external-ref?access_num=000175412100014&link_type=ISI [30]: #xref-ref-5-1 "View reference 5 in text" [31]: {openurl}?query=rft.jtitle%253DCold%2BSpring%2BHarb.%2BPerspect.%2BBiol.%26rft_id%253Dinfo%253Adoi%252F10.1101%252Fcshperspect.a005710%26rft_id%253Dinfo%253Apmid%252F22510460%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [32]: /lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6MTE6ImNzaHBlcnNwZWN0IjtzOjU6InJlc2lkIjtzOjExOiI0LzYvYTAwNTcxMCI7czo0OiJhdG9tIjtzOjIyOiIvc2NpLzM3MC82NTEzLzE2OC5hdG9tIjt9czo4OiJmcmFnbWVudCI7czowOiIiO30= [33]: #xref-ref-6-1 "View reference 6 in text" [34]: {openurl}?query=rft.jtitle%253DNature%2Breviews.%2BNeuroscience%26rft.stitle%253DNat%2BRev%2BNeurosci%26rft.aulast%253DHardingham%26rft.auinit1%253DG.%2BE.%26rft.volume%253D11%26rft.issue%253D10%26rft.spage%253D682%26rft.epage%253D696%26rft.atitle%253DSynaptic%2Bversus%2Bextrasynaptic%2BNMDA%2Breceptor%2Bsignalling%253A%2Bimplications%2Bfor%2Bneurodegenerative%2Bdisorders.%26rft_id%253Dinfo%253Adoi%252F10.1038%252Fnrn2911%26rft_id%253Dinfo%253Apmid%252F20842175%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [35]: /lookup/external-ref?access_num=10.1038/nrn2911&link_type=DOI [36]: /lookup/external-ref?access_num=20842175&link_type=MED&atom=%2Fsci%2F370%2F6513%2F168.atom [37]: /lookup/external-ref?access_num=000281928500002&link_type=ISI [38]: #xref-ref-7-1 "View reference 7 in text" [39]: {openurl}?query=rft.jtitle%253DCell%2Bcalcium%26rft.stitle%253DCell%2BCalcium%26rft.aulast%253DArundine%26rft.auinit1%253DM.%26rft.volume%253D34%26rft.issue%253D4-5%26rft.spage%253D325%26rft.epage%253D337%26rft.atitle%253DMolecular%2Bmechanisms%2Bof%2Bcalcium-dependent%2Bneurodegeneration%2Bin%2Bexcitotoxicity.%26rft_id%253Dinfo%253Adoi%252F10.1016%252FS0143-4160%252803%252900141-6%26rft_id%253Dinfo%253Apmid%252F12909079%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [40]: /lookup/external-ref?access_num=10.1016/S0143-4160(03)00141-6&link_type=DOI [41]: /lookup/external-ref?access_num=12909079&link_type=MED&atom=%2Fsci%2F370%2F6513%2F168.atom [42]: /lookup/external-ref?access_num=000184927500003&link_type=ISI [43]: #xref-ref-8-1 "View reference 8 in text" [44]: {openurl}?query=rft.jtitle%253DFront.%2BNeurosci.%26rft.volume%253D9%26rft.spage%253D469%26rft_id%253Dinfo%253Adoi%252F10.3389%252Ffnins.2015.00469%26rft_id%253Dinfo%253Apmid%252F26733784%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [45]: /lookup/external-ref?access_num=10.3389/fnins.2015.00469&link_type=DOI [46]: /lookup/external-ref?access_num=26733784&link_type=MED&atom=%2Fsci%2F370%2F6513%2F168.atom [47]: #xref-ref-9-1 "View reference 9 in text" [48]: #xref-ref-10-1 "View reference 10 in text" [49]: {openurl}?query=rft.jtitle%253DNature%2Bmedicine%26rft.stitle%253DNat%2BMed%26rft.aulast%253DSchattling%26rft.auinit1%253DB.%26rft.volume%253D18%26rft.spage%253D1805%26rft.atitle%253DTRPM4%2Bcation%2Bchannel%2Bmediates%2Baxonal%2Band%2Bneuronal%2Bdegeneration%2Bin%2Bexperimental%2Bautoimmune%2Bencephalomyelitis%2Band%2Bmultiple%2Bsclerosis.%26rft_id%253Dinfo%253Adoi%252F10.1038%252Fnm.3015%26rft_id%253Dinfo%253Apmid%252F23160238%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [50]: /lookup/external-ref?access_num=10.1038/nm.3015&link_type=DOI [51]: /lookup/external-ref?access_num=23160238&link_type=MED&atom=%2Fsci%2F370%2F6513%2F168.atom [52]: #xref-ref-11-1 "View reference 11 in text" [53]: {openurl}?query=rft.jtitle%253DNeuropharmacology%26rft.volume%253D74%26rft.spage%253D4%26rft_id%253Dinfo%253Adoi%252F10.1016%252Fj.neuropharm.2013.01.016%26rft_id%253Dinfo%253Apmid%252F23376022%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [54]: /lookup/external-ref?access_num=10.1016/j.neuropharm.2013.01.016&link_type=DOI [55]: /lookup/external-ref?access_num=23376022&link_type=MED&atom=%2Fsci%2F370%2F6513%2F168.atom [56]: #xref-ref-12-1 "View reference 12 in text" [57]: {openurl}?query=rft.jtitle%253DNature%2Bneuroscience%26rft.stitle%253DNat%2BNeurosci%26rft.aulast%253DHardingham%26rft.auinit1%253DG.%2BE.%26rft.volume%253D5%26rft.issue%253D5%26rft.spage%253D405%26rft.epage%253D414%26rft.atitle%253DExtrasynaptic%2BNMDARs%2Boppose%2Bsynaptic%2BNMDARs%2Bby%2Btriggering%2BCREB%2Bshut-off%2Band%2Bcell%2Bdeath%2Bpathways.%26rft_id%253Dinfo%253Adoi%252F10.1038%252Fnn835%26rft_id%253Dinfo%253Apmid%252F11953750%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [58]: /lookup/external-ref?access_num=10.1038/nn835&link_type=DOI [59]: /lookup/external-ref?access_num=11953750&link_type=MED&atom=%2Fsci%2F370%2F6513%2F168.atom [60]: /lookup/external-ref?access_num=000175272000010&link_type=ISI [61]: #xref-ref-13-1 "View reference 13 in text" [62]: {openurl}?query=rft.jtitle%253DNature%2Breviews.%2BDrug%2Bdiscovery%26rft.stitle%253DNat%2BRev%2BDrug%2BDiscov%26rft.aulast%253DLipton%26rft.auinit1%253DS.%2BA.%26rft.volume%253D5%26rft.issue%253D2%26rft.spage%253D160%26rft.epage%253D170%26rft.atitle%253DParadigm%2Bshift%2Bin%2Bneuroprotection%2Bby%2BNMDA%2Breceptor%2Bblockade%253A%2Bmemantine%2Band%2Bbeyond.%26rft_id%253Dinfo%253Adoi%252F10.1038%252Fnrd1958%26rft_id%253Dinfo%253Apmid%252F16424917%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [63]: /lookup/external-ref?access_num=10.1038/nrd1958&link_type=DOI [64]: /lookup/external-ref?access_num=16424917&link_type=MED&atom=%2Fsci%2F370%2F6513%2F168.atom [65]: /lookup/external-ref?access_num=000235067900028&link_type=ISI [66]: #xref-ref-14-1 "View reference 14 in text" [67]: {openurl}?query=rft.jtitle%253DNeuron%26rft.volume%253D82%26rft.spage%253D279%26rft_id%253Dinfo%253Adoi%252F10.1016%252Fj.neuron.2014.03.030%26rft_id%253Dinfo%253Apmid%252F24742457%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [68]: /lookup/external-ref?access_num=10.1016/j.neuron.2014.03.030&link_type=DOI [69]: /lookup/external-ref?access_num=24742457&link_type=MED&atom=%2Fsci%2F370%2F6513%2F168.atom [70]: /lookup/external-ref?access_num=000334506800006&link_type=ISI
领域	气候变化 ; 资源环境
URL	查看原文
引用统计
文献类型	期刊论文
条目标识符	http://119.78.100.173/C666/handle/2XK7JSWQ/298085
专题	气候变化资源环境科学
推荐引用方式 GB/T 7714	Susan Jones. A new villain in neuronal death[J]. Science,2020.
APA	Susan Jones.(2020).A new villain in neuronal death.Science.
MLA	Susan Jones."A new villain in neuronal death".Science (2020).