Nicotine preconditioning antagonizes activity-dependent caspase proteolysis of a glutamate receptor.
Neuronal excitation is required for normal brain function including processes of learning and memory, yet if this process becomes dysregulated there is reduced neurotransmission and possibly death through excitotoxicity. Nicotine, through interaction with neuronal nicotinic acetylcholine receptors, possesses the ability to modulate neurotransmitter systems through numerous mechanisms that define this critical balance. We examined the modulatory role of nicotine in primary mixed cortical neuronal-glial cultures on activity-dependent caspase cleavage of a glutamate receptor, GluR1. We find that GluR1, but not GluR2 or GluR3, is a substrate for agonist (alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid)-initiated rapid proteolytic cleavage at aspartic acid 865 through the activation of caspase 8-like activity that is independent of membrane fusion and is not coincident with apoptosis. Dose-dependent nicotine preconditioning for 24 h antagonizes agonist-initiated caspase cleavage of GluR1 through a mechanism that is coincident with desensitization of both nAChRalpha4beta2 and nAChRalpha7 receptors and the delayed activation of a caspase 8-like activity. The modulation of GluR1 agonist-initiated caspase-mediated cleavage by nicotine preconditioning offers a novel insight into how this agent can impart its numerous effects on the nervous system.
Meyer
Erin L
EL
Salt Lake City Veterans Affairs-Geriatrics Research, Education, and Clinical Center and the University of Utah School of Medicine, Salt Lake City, Utah 84132, USA.
Gahring
Lorise C
LC
Rogers
Scott W
SW
D000818:Animals; D017209:Apoptosis; D053181:Caspase 8; D053453:Caspase 9; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D006868:Hydrolysis; D051379:Mice; D009538:Nicotine / Q000494:pharmacology*; D018091:Receptors, AMPA / Q000187:drug effects* / Q000378:metabolism; D013379:Substrate Specificity
D053181:Caspase 8; D053453:Caspase 9; D061945:Caspase Inhibitors; D020169:Caspases; D015853:Cysteine Proteinase Inhibitors; D009538:Nicotine; D018091:Receptors, AMPA; C505526:Casp8 protein, mouse; C506434:Casp9 protein, mouse