title: Genetic evidence for adenylyl cyclase 1 as a target for preventing neuronal excitotoxicity mediated by N-methyl-D-aspartate receptors.
abstract: The excessive activation of N-methyl-D-aspartate (NMDA) receptors by glutamate results in neuronal excitotoxicity. cAMP is a key second messenger and contributes to NMDA receptor-dependent synaptic plasticity. Adenylyl cyclases 1 (AC1) and 8 (AC8) are the two major calcium-stimulated ACs in the central nervous system. Previous studies demonstrate AC1 and AC8 play important roles in synaptic plasticity, memory, and persistent pain. However, little is known about the possible roles of these two ACs in glutamate-induced neuronal excitotoxicity. Here, we report that genetic deletion of AC1 significantly attenuated neuronal death induced by glutamate in primary cultures of cortical neurons, whereas AC8 deletion did not produce a significant effect. AC1, but not AC8, contributes to intracellular cAMP production following NMDA receptor activation by glutamate in cultured cortical neurons. AC1 is involved in the dynamic modulation of cAMP-response element-binding protein activity in neuronal excitotoxicity. To explore the possible roles of AC1 in cell death in vivo, we studied neuronal excitotoxicity induced by an intracortical injection of NMDA. Cortical lesions induced by NMDA were significantly reduced in AC1 but not in AC8 knock-out mice. Our findings provide direct evidence that AC1 plays an important role in neuronal excitotoxicity and may serve as a therapeutic target for preventing excitotoxicity in stroke and neurodegenerative diseases.
authors.affiliation: Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
authors.forename: Hansen
authors.initials: H
authors.lastname: Wang
authors.forename: Bo
authors.initials: B
authors.lastname: Gong
authors.forename: Kunjumon I
authors.initials: KI
authors.lastname: Vadakkan
authors.forename: Hiroki
authors.initials: H
authors.lastname: Toyoda
authors.forename: Bong-Kiun
authors.initials: BK
authors.lastname: Kaang
authors.forename: Min
authors.initials: M
authors.lastname: Zhuo
mesh_terms: D000262:Adenylyl Cyclases / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D016923:Cell Death / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D000242:Cyclic AMP / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D017353:Gene Deletion; D018698:Glutamic Acid / Q000633:toxicity; D051379:Mice; D018345:Mice, Knockout; D019636:Neurodegenerative Diseases / Q000378:metabolism / Q000517:prevention & control; D009474:Neurons / Q000166:cytology / Q000201:enzymology*; D009498:Neurotoxins / Q000378:metabolism* / Q000633:toxicity; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists / Q000378:metabolism*; D011985:Receptors, Serotonin / Q000378:metabolism; D020521:Stroke / Q000378:metabolism / Q000517:prevention & control
chemical_list: C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D009498:Neurotoxins; D016194:Receptors, N-Methyl-D-Aspartate; D011985:Receptors, Serotonin; C104425:serotonin 7 receptor; D018698:Glutamic Acid; D000242:Cyclic AMP; D000262:Adenylyl Cyclases; C106670:adenylyl cyclase 1; C118292:adenylyl cyclase 8