Gemma Navarro*, Iu Raïch, Joan Biel Rebassa, Jaume Lillo, Catalina Pérez-Olives, Toni Capó, Erik Cubeles, Carlos A. Saura, Arnau Cordomí, Eddy Sotelo, Irene Reyes-Resina and Rafael Franco*,
{"title":"大麻素CB1受体激活减轻n -甲基-d-天冬氨酸受体介导的神经毒性","authors":"Gemma Navarro*, Iu Raïch, Joan Biel Rebassa, Jaume Lillo, Catalina Pérez-Olives, Toni Capó, Erik Cubeles, Carlos A. Saura, Arnau Cordomí, Eddy Sotelo, Irene Reyes-Resina and Rafael Franco*, ","doi":"10.1021/acsptsci.5c00230","DOIUrl":null,"url":null,"abstract":"<p >Alzheimer’s disease (AD) is characterized by synaptic dysfunction and excitotoxicity, yet effective therapeutic strategies remain limited. This study explores the functional and physical interplay between cannabinoid CB<sub>1</sub> receptors (CB<sub>1</sub>Rs) and <i>N</i>-methyl-<span>d</span>-aspartate receptors (NMDARs), which are implicated in AD pathology. Using bioluminescence resonance energy transfer and imaging assays in HEK-293T cells, we demonstrate a direct interaction between CB<sub>1</sub>R and the N1 subunit of NMDAR, supporting the formation of receptor complexes. Functional assays further reveal a bidirectional negative crosstalk: NMDA attenuates CB<sub>1</sub>R-mediated cAMP inhibition, while CB<sub>1</sub>R activation reduces NMDA-induced calcium influx and mitogen-activated protein kinase signaling pathway activation. This negative crosstalk suggests the existence of receptor–receptor interactions with functional consequences. Complexes of CB<sub>1</sub>Rs and N<sub>1</sub> subunits of NMDARs are present in both neurons and microglia, and their expression is upregulated in response to Aβ<sub>1–42</sub> and in cells derived from the APP<sub>Sw/Ind</sub> AD model mice. However, upregulation did not always correlate with stronger CB<sub>1</sub>R–NMDAR cross-modulation, suggesting that cell-specific signalosome composition shapes the signaling outcome. Functionally, CB<sub>1</sub>R activation confers neuroprotection: It rescues neurite loss induced by NMDA and Aβ<sub>1–42</sub>, highlighting the therapeutic potential of modulating CB<sub>1</sub>R–NMDAR interactions. These findings support a model in which CB<sub>1</sub>R–NMDAR interactions, through dynamic functional cross-modulation, finely tune excitotoxic and inflammatory signaling pathways. This mechanism offers therapeutic prospects for addressing cannabinoid-glutamatergic interactions.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 9","pages":"3019–3032"},"PeriodicalIF":3.7000,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acsptsci.5c00230","citationCount":"0","resultStr":"{\"title\":\"Cannabinoid CB1 Receptor Activation Mitigates N-Methyl-d-aspartate Receptor-Mediated Neurotoxicity\",\"authors\":\"Gemma Navarro*, Iu Raïch, Joan Biel Rebassa, Jaume Lillo, Catalina Pérez-Olives, Toni Capó, Erik Cubeles, Carlos A. Saura, Arnau Cordomí, Eddy Sotelo, Irene Reyes-Resina and Rafael Franco*, \",\"doi\":\"10.1021/acsptsci.5c00230\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p >Alzheimer’s disease (AD) is characterized by synaptic dysfunction and excitotoxicity, yet effective therapeutic strategies remain limited. This study explores the functional and physical interplay between cannabinoid CB<sub>1</sub> receptors (CB<sub>1</sub>Rs) and <i>N</i>-methyl-<span>d</span>-aspartate receptors (NMDARs), which are implicated in AD pathology. Using bioluminescence resonance energy transfer and imaging assays in HEK-293T cells, we demonstrate a direct interaction between CB<sub>1</sub>R and the N1 subunit of NMDAR, supporting the formation of receptor complexes. Functional assays further reveal a bidirectional negative crosstalk: NMDA attenuates CB<sub>1</sub>R-mediated cAMP inhibition, while CB<sub>1</sub>R activation reduces NMDA-induced calcium influx and mitogen-activated protein kinase signaling pathway activation. This negative crosstalk suggests the existence of receptor–receptor interactions with functional consequences. Complexes of CB<sub>1</sub>Rs and N<sub>1</sub> subunits of NMDARs are present in both neurons and microglia, and their expression is upregulated in response to Aβ<sub>1–42</sub> and in cells derived from the APP<sub>Sw/Ind</sub> AD model mice. However, upregulation did not always correlate with stronger CB<sub>1</sub>R–NMDAR cross-modulation, suggesting that cell-specific signalosome composition shapes the signaling outcome. Functionally, CB<sub>1</sub>R activation confers neuroprotection: It rescues neurite loss induced by NMDA and Aβ<sub>1–42</sub>, highlighting the therapeutic potential of modulating CB<sub>1</sub>R–NMDAR interactions. These findings support a model in which CB<sub>1</sub>R–NMDAR interactions, through dynamic functional cross-modulation, finely tune excitotoxic and inflammatory signaling pathways. This mechanism offers therapeutic prospects for addressing cannabinoid-glutamatergic interactions.</p>\",\"PeriodicalId\":36426,\"journal\":{\"name\":\"ACS Pharmacology and Translational Science\",\"volume\":\"8 9\",\"pages\":\"3019–3032\"},\"PeriodicalIF\":3.7000,\"publicationDate\":\"2025-08-25\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://pubs.acs.org/doi/pdf/10.1021/acsptsci.5c00230\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"ACS Pharmacology and Translational Science\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://pubs.acs.org/doi/10.1021/acsptsci.5c00230\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CHEMISTRY, MEDICINAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"ACS Pharmacology and Translational Science","FirstCategoryId":"1085","ListUrlMain":"https://pubs.acs.org/doi/10.1021/acsptsci.5c00230","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
Alzheimer’s disease (AD) is characterized by synaptic dysfunction and excitotoxicity, yet effective therapeutic strategies remain limited. This study explores the functional and physical interplay between cannabinoid CB1 receptors (CB1Rs) and N-methyl-d-aspartate receptors (NMDARs), which are implicated in AD pathology. Using bioluminescence resonance energy transfer and imaging assays in HEK-293T cells, we demonstrate a direct interaction between CB1R and the N1 subunit of NMDAR, supporting the formation of receptor complexes. Functional assays further reveal a bidirectional negative crosstalk: NMDA attenuates CB1R-mediated cAMP inhibition, while CB1R activation reduces NMDA-induced calcium influx and mitogen-activated protein kinase signaling pathway activation. This negative crosstalk suggests the existence of receptor–receptor interactions with functional consequences. Complexes of CB1Rs and N1 subunits of NMDARs are present in both neurons and microglia, and their expression is upregulated in response to Aβ1–42 and in cells derived from the APPSw/Ind AD model mice. However, upregulation did not always correlate with stronger CB1R–NMDAR cross-modulation, suggesting that cell-specific signalosome composition shapes the signaling outcome. Functionally, CB1R activation confers neuroprotection: It rescues neurite loss induced by NMDA and Aβ1–42, highlighting the therapeutic potential of modulating CB1R–NMDAR interactions. These findings support a model in which CB1R–NMDAR interactions, through dynamic functional cross-modulation, finely tune excitotoxic and inflammatory signaling pathways. This mechanism offers therapeutic prospects for addressing cannabinoid-glutamatergic interactions.
期刊介绍:
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