N-Methyl-D-aspartate (NMDA) and cannabinoid CB2 receptors form functional complexes in cells of the central nervous system: insights into the therapeutic potential of neuronal and microglial NMDA receptors
Tóm tắt
The cannabinoid CB2 receptor (CB2R), which is a target to afford neuroprotection, and N-methyl-D-aspartate (NMDA) ionotropic glutamate receptors, which are key in mediating excitatory neurotransmission, are expressed in both neurons and glia. As NMDA receptors are the target of current medication in Alzheimer’s disease patients and with the aim of finding neuromodulators of their actions that could provide benefits in dementia, we hypothesized that cannabinoids could modulate NMDA function. Immunocytochemistry was used to analyze the colocalization between CB2 and NMDA receptors; bioluminescence resonance energy transfer was used to detect CB2-NMDA receptor complexes. Calcium and cAMP determination, mitogen-activated protein kinase (MAPK) pathway activation, and label-free assays were performed to characterize signaling in homologous and heterologous systems. Proximity ligation assays were used to quantify CB2-NMDA heteromer expression in mouse primary cultures and in the brain of APPSw/Ind transgenic mice, an Alzheimer’s disease model expressing the Indiana and Swedish mutated version of the human amyloid precursor protein (APP). In a heterologous system, we identified CB2-NMDA complexes with a particular heteromer print consisting of impairment by cannabinoids of NMDA receptor function. The print was detected in activated primary microglia treated with lipopolysaccharide and interferon-γ. CB2R activation blunted NMDA receptor-mediated signaling in primary hippocampal neurons from APPSw/Ind mice. Furthermore, imaging studies showed that in brain slices and in primary cells (microglia or neurons) from APPSw/Ind mice, there was a marked overexpression of macromolecular CB2-NMDA receptor complexes thus becoming a tool to modulate excessive glutamate input by cannabinoids. The results indicate a negative cross-talk in CB2-NMDA complexes signaling. The expression of the CB2-NMDA receptor heteromers increases in both microglia and neurons from the APPSw/Ind transgenic mice, compared with levels in samples from age-matched control mice.
Tài liệu tham khảo
Arendt T, Zveuintshva HG, Lkontovich TA. Dendritic changes in the basal nucleus of meynert and in the diagonal band nucleus in Alzheimer’s disease-A quantitative Golgi investigation. Neuroscience. 1986;19. https://doi.org/10.1016/0306-4522(86)90141-7.
Doucette R, Fisman M, Hachinski VC, Mersky H. Cell Loss from the Nucleus Basalis of Meynert in Alzheimer’s Disease. Can. J. Neurol. Sci. / J. Can. des Sci. Neurol. 1986;13:435–40. https://doi.org/10.1017/S0317167100037070.
Etienne P, Robitaille Y, Wood P, Gauthier S, Nair NPV, Quirion R. Nucleus basalis neuronal loss, neuritic plaques and choline acetyltransferase activity in advanced Alzheimer’s disease. Neuroscience. 1986;19:1279–91. https://doi.org/10.1016/0306-4522(86)90142-9.
Wang Q, Li W-X, Dai S-X, Guo Y-C, Han F-F, Zheng J-J, et al. Meta-Analysis of Parkinson’s Disease and Alzheimer’s Disease Revealed Commonly Impaired Pathways and Dysregulation of NRF2-Dependent Genes. J. Alzheimers. Dis. 2017;56:1525–39. https://doi.org/10.3233/JAD-161032.
Wang R, Reddy PH. Role of Glutamate and NMDA Receptors in Alzheimer’s Disease. J. Alzheimer’s Dis. 2017;57:1041–8. https://doi.org/10.3233/JAD-160763.
Lipton S. Pathologically-Activated Therapeutics for Neuroprotection: Mechanism of NMDA Receptor Block by Memantine and S-Nitrosylation. Curr Drug Targets. 2007;8:621–32. https://doi.org/10.2174/138945007780618472.
Lipton SA. Paradigm shift in neuroprotection by NMDA receptor blockade: Memantine and beyond. Nat. Rev. Drug Discov. 2006;5:160–70. https://doi.org/10.1038/nrd1958.
Alexander SPH, Mathie A, Peters JA, Veale EL, Striessnig J, Kelly E, et al. The concise guide to pharmacology 2019/20: Ion channels. Br. J. Pharmacol. 2019;176:S142–228. https://doi.org/10.1111/bph.14749.
Stazi M, Wirths O. Chronic Memantine Treatment Ameliorates Behavioral Deficits, Neuron Loss, and Impaired Neurogenesis in a Model of Alzheimer’s Disease. Mol. Neurobiol. 2021;58:204–16. https://doi.org/10.1007/s12035-020-02120-z.
Lanciego JL, Barroso-Chinea P, Rico AJ, Conte-Perales L, Callén L, Roda E, et al. Expression of the mRNA coding the cannabinoid receptor 2 in the pallidal complex of Macaca fascicularis. J. Psychopharmacol. 2011a;25:97–104. https://doi.org/10.1177/0269881110367732.
Ashton JC, Friberg D, Darlington CL, Smith PF. Expression of the cannabinoid CB2 receptor in the rat cerebellum: an immunohistochemical study. Neurosci. Lett. 2006;396:113–6. https://doi.org/10.1016/j.neulet.2005.11.038.
Chung YC, Shin W-HH, Baek JY, Cho EJ, Baik HH, Kim SR, et al. CB2 receptor activation prevents glial-derived neurotoxic mediator production, BBB leakage and peripheral immune cell infiltration and rescues dopamine neurons in the MPTP model of Parkinson’s disease. Exp. Mol. Med. 2016;48:e205. https://doi.org/10.1038/emm.2015.100.
Navarro G, Morales P, Rodríguez-Cueto C, Fernández-Ruiz J, Jagerovic N, Franco R. Targeting Cannabinoid CB2 Receptors in the Central Nervous System. Medicinal Chemistry Approaches with Focus on Neurodegenerative Disorders. Front. Neurosci. 2016;10. https://doi.org/10.3389/fnins.2016.00406.
Pazos MRR, Mohammed N, Lafuente H, Santos M, Martínez-Pinilla E, Moreno E, et al. Mechanisms of cannabidiol neuroprotection in hypoxic-ischemic newborn pigs: Role of 5HT1A and CB2 receptors. Neuropharmacology. 2013;71:282–91. https://doi.org/10.1016/j.neuropharm.2013.03.027.
Reyes-Resina I, Navarro G, Aguinaga D, Canela EI, Schoeder CT, Załuski M, et al. Molecular and functional interaction between GPR18 and cannabinoid CB2 G-protein-coupled receptors. Relevance in neurodegenerative diseases. Biochem. Pharmacol. 2018;157:169–79. https://doi.org/10.1016/j.bcp.2018.06.001.
Stella N. Cannabinoid and cannabinoid-like receptors in microglia, astrocytes, and astrocytomas. Glia. 2010;58:1017–30. https://doi.org/10.1002/glia.20983.
Wu J, Bie B, Yang H, Xu JJ, Brown DL, Naguib M. Activation of the CB2 receptor system reverses amyloid-induced memory deficiency. Neurobiol. Aging. 2013;34:791–804. https://doi.org/10.1016/j.neurobiolaging.2012.06.011.
Borroto-Escuela DO, Brito I, Romero-Fernandez W, Di Palma M, Oflijan J, Skieterska K, et al. The G protein-coupled receptor heterodimer network (GPCR-HetNet) and its hub components. Int. J. Mol. Sci. 2014;15:8570–90. https://doi.org/10.3390/ijms15058570.
Ferré S, Baler R, Bouvier M, Caron MG, Devi LA, Durroux T, et al. Building a new conceptual framework for receptor heteromers. Nat. Chem. Biol. 2009;5:131–4. https://doi.org/10.1038/nchembio0309-131.
Callén L, Moreno E, Barroso-Chinea P, Moreno-Delgado D, Cortés A, Mallol J, et al. Cannabinoid receptors CB1 and CB2 form functional heteromers in brain. J. Biol. Chem. 2012;287:20851–65. https://doi.org/10.1074/jbc.M111.335273.
Sierra S, Luquin N, Rico AJ, Gómez-Bautista V, Roda E, Dopeso-Reyes IG, et al. Detection of cannabinoid receptors CB1 and CB2 within basal ganglia output neurons in macaques: changes following experimental parkinsonism. Brain Struct. Funct. 2015;220:2721–38. https://doi.org/10.1007/s00429-014-0823-8.
Navarro G, Borroto-Escuela D, Angelats E, Etayo I, Reyes-Resina I, Pulido-Salgado M, et al. Receptor-heteromer mediated regulation of endocannabinoid signaling in activated microglia. Role of CB1 and CB2 receptors and relevance for Alzheimer’s disease and levodopa-induced dyskinesia. Brain. Behav. Immun. 2018;67:139–51. https://doi.org/10.1016/j.bbi.2017.08.015.
Cilia, R. (2018). “Molecular Imaging of the Cannabinoid System in Idiopathic Parkinson’s Disease,” in International review of neurobiology, 305–345. doi:https://doi.org/10.1016/bs.irn.2018.08.004.
Fernández-López D, Pazos MR, Tolón RM, Moro MA, Romero J, Lizasoain I, et al. The cannabinoid agonist WIN55212 reduces brain damage in an in vivo model of hypoxic-ischemic encephalopathy in newborn rats. Pediatr. Res. 2007;62:255–60. https://doi.org/10.1203/PDR.0b013e318123fbb8.
Micale V, Mazzola C, Drago F. Endocannabinoids and neurodegenerative diseases. Pharmacol. Res. 2007;56:382–92. https://doi.org/10.1016/j.phrs.2007.09.008.
Rodríguez-Cueto C, Santos-García I, García-Toscano L, Espejo-Porras F, Bellido M, Fernández-Ruiz J, et al. Neuroprotective effects of the cannabigerol quinone derivative VCE-003.2 in SOD1G93A transgenic mice, an experimental model of amyotrophic lateral sclerosis. Biochem. Pharmacol. 2018;157:217–26. https://doi.org/10.1016/j.bcp.2018.07.049.
Sánchez AJ, García-Merino A. Neuroprotective agents: Cannabinoids. Clin. Immunol. 2012;142:57–67. https://doi.org/10.1016/j.clim.2011.02.010.
Franco, R., Aguinaga, D., Reyes, I., Canela, E. I., Lillo, J., Tarutani, A., et al. (2018b). N-Methyl-D-Aspartate Receptor Link to the MAP Kinase Pathway in Cortical and Hippocampal Neurons and Microglia Is Dependent on Calcium Sensors and Is Blocked by α-Synuclein, Tau, and Phospho-Tau in Non-transgenic and Transgenic APPSw,Ind Mice. Front. Mol. Neurosci. 11, 273. doi:https://doi.org/10.3389/fnmol.2018.00273.
Franco R, Rivas-Santisteban R, Casanovas M, Lillo A, Saura CA, Navarro G. Adenosine A2A Receptor Antagonists Affects NMDA Glutamate Receptor Function. Potential to Address Neurodegeneration in Alzheimer’s Disease. Cells. 2020;9. https://doi.org/10.3390/cells9051075.
Rodríguez-Ruiz M, Moreno E, Moreno-Delgado D, Navarro G, Mallol J, Cortés A, et al. Heteroreceptor Complexes Formed by Dopamine D1, Histamine H3, and N-Methyl-D-Aspartate Glutamate Receptors as Targets to Prevent Neuronal Death in Alzheimer’s Disease. Mol. Neurobiol. 2017;54:4537–50. https://doi.org/10.1007/s12035-016-9995-y.
Choi D, Koh J, Peters S. Pharmacology of glutamate neurotoxicity in cortical cell culture: attenuation by NMDA antagonists. J. Neurosci. 1988;8:185–96. https://doi.org/10.1523/JNEUROSCI.08-01-00185.1988.
Yuzaki M, Miyawaki A, Akita K, Kudo Y, Ogura A, Ino H, et al. Mode of blockade by MK-801 of N-methyl-d-aspartate-induced increase in intracellular Ca2+ in cultured mouse hippocampal neurons. Brain Res. 1990;517:51–6. https://doi.org/10.1016/0006-8993(90)91006-3.
Codd EE, Mabus JR, Murray BS, Zhang SP, Flores CM. Dynamic mass redistribution as a means to measure and differentiate signaling via opioid and cannabinoid receptors. Assay Drug Dev. Technol. 2011;9:362–72. https://doi.org/10.1089/adt.2010.0347.
Franco R, Aguinaga D, Jiménez J, Lillo J, Martínez-Pinilla E, Navarro G. Biased receptor functionality versus biased agonism in G-protein-coupled receptors. Biomol. Concepts. 2018a;9:143–54. https://doi.org/10.1515/bmc-2018-0013.
Franco R, Martínez-Pinilla E, Lanciego JL, Navarro G. Basic pharmacological and structural evidence for class A G-protein-coupled receptor heteromerization. Front. Pharmacol. 2016;7:1–10. https://doi.org/10.3389/fphar.2016.00076.
Alvarez FJ, Lafuente H, Rey-Santano MC, Mielgo VE, Gastiasoro E, Rueda M, et al. Neuroprotective effects of the nonpsychoactive cannabinoid cannabidiol in hypoxic-ischemic newborn piglets. Pediatr. Res. 2008;64:653–8. https://doi.org/10.1203/PDR.0b013e318186e5dd.
Fernández-Ruiz J, Sagredo O, Pazos MR, García C, Pertwee R, Mechoulam R, et al. Cannabidiol for neurodegenerative disorders: important new clinical applications for this phytocannabinoid? Br. J. Clin. Pharmacol. 2013;75:323–33. https://doi.org/10.1111/j.1365-2125.2012.04341.x.
van der Stelt M, Di Marzo V. Cannabinoid receptors and their role in neuroprotection. Neuromolecular Med. 2005;7:37–50. https://doi.org/10.1385/NMM:7:1-2:037.
Lewerenz J, Maher P. Chronic glutamate toxicity in neurodegenerative diseases-What is the evidence? Front. Neurosci. 2015;9. https://doi.org/10.3389/fnins.2015.00469.
Navarro G, Varani K, Lillo A, Vincenzi F, Rivas-Santisteban R, Raïch I, et al. Pharmacological data of cannabidiol- and cannabigerol-type phytocannabinoids acting on cannabinoid CB1, CB2 and CB1/CB2 heteromer receptors. Pharmacol. Res. 2020;159:104940. https://doi.org/10.1016/j.phrs.2020.104940.
Morales P, Navarro G, Gómez-Autet M, Redondo L, Fernández-Ruiz J, Pérez-Benito L, et al. Discovery of Homobivalent Bitopic Ligands of the Cannabinoid CB2 Receptor**. Chem. - A Eur. J. 2020;26:15839–42. https://doi.org/10.1002/chem.202003389.
Pérez M, Valpuesta JM, Medina M, Montejo de Garcini E, Avila J. Polymerization of τ into Filaments in the Presence of Heparin: The Minimal Sequence Required for τ - τ Interaction. J. Neurochem. 2002;67:1183–90. https://doi.org/10.1046/j.1471-4159.1996.67031183.x.
Tarutani A, Suzuki G, Shimozawa A, Nonaka T, Akiyama H, Hisanaga SI, et al. The effect of fragmented pathogenic α-synuclein seeds on prion-like propagation. J. Biol. Chem. 2016;291:18675–88. https://doi.org/10.1074/jbc.M116.734707.
Newell, E., Exo, J., Verrier, J., Jackson, T., Gillespie, D., K Janesko-Feldman, et al. (2015). 2’,3’-cAMP, 3’-AMP, 2’-AMP and adenosine inhibit TNF-α and CXCL10 production from activated primary murine microglia via A2A receptors. Brain Res. 1594, 27–35. doi: https://doi.org/10.1016/j.brainres.2014.10.059.
Hradsky J, Mikhaylova M, Karpova A, Kreutz MR, Zuschratter W. Super-resolution microscopy of the neuronal calcium-binding proteins Calneuron-1 and Caldendrin. Methods Mol. Biol. 2013;963:147–69. https://doi.org/10.1007/978-1-62703-230-8_10.
Mucke, L., Masliah, E., Yu, G. Q., Mallory, M., Rockenstein, E. M., Tatsuno, G., et al. (2000). High-level neuronal expression of abeta 1-42 in wild-type human amyloid protein precursor transgenic mice: synaptotoxicity without plaque formation. J. Neurosci. 20, 4050–8. doi:20/11/4050 [pii].
Chen T-W, Wardill TJ, Sun Y, Pulver SR, Renninger SL, Baohan A, et al. Ultrasensitive fluorescent proteins for imaging neuronal activity. Nature. 2013;499:295–300. https://doi.org/10.1038/nature12354.
Law AMK, Yin JXM, Castillo L, Young AIJ, Piggin C, Rogers S, et al. Andy’s Algorithms: new automated digital image analysis pipelines for FIJI. Sci. Rep. 2017;7:15717. https://doi.org/10.1038/s41598-017-15885-6.