Neuroprotection by nicotine in mouse primary cortical cultures involves activation of calcineurin and L-type calcium channel inactivation.
Regulation of intracellular calcium influences neuronal excitability, synaptic plasticity, gene expression, and neurotoxicity. In this study, we investigated the role of calcium in mechanisms underlying nicotine-mediated neuroprotection from glutamate excitotoxicity. Neuroprotection by nicotine in primary cortical cultures was not seen in knock-out mice lacking the beta2 subunit of the nicotinic acetylcholine receptor (nAChR). Neuroprotection was partially blocked in wild-type cultures by alpha-bungarotoxin, an antagonist of the alpha7 nAChR subtype, suggesting a potential cooperative role for these subtypes. Pretreatment with nicotine decreased glutamate-mediated calcium influx in primary cortical cultures by 41%, an effect that was absent in cultures from knock-out mice lacking the beta2 subunit of the nAChR. This effect was dependent on calcium entry through L-type channels during nicotine pretreatment in wild-type cultures. The ability of nicotine to decrease glutamate-mediated calcium influx was occluded by cotreatment with nifedipine during glutamate application, suggesting that nicotine pretreatment decreased subsequent activity of L-type calcium channels. Treatment with the calcineurin antagonists FK506 and cyclosporine during pretreatment eliminated both nicotine-mediated neuroprotection and the effects of nicotine on L-type channels. We conclude that neuroprotective effects of nicotine in cortical neurons involve both beta2- and alpha7-containing nAChRs, activation of calcineurin, and decreased intracellular calcium via L-type channels.
Stevens
Tanya R
TR
Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut 06508, USA.
Krueger
Stefan R
SR
Fitzsimonds
Reiko M
RM
Picciotto
Marina R
MR
D000818:Animals; D002038:Bungarotoxins / Q000494:pharmacology; D019703:Calcineurin / Q000378:metabolism*; D065095:Calcineurin Inhibitors; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000187:drug effects* / Q000378:metabolism; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D018698:Glutamic Acid / Q000633:toxicity; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009498:Neurotoxins / Q000633:toxicity; D009538:Nicotine / Q000494:pharmacology*; D009543:Nifedipine / Q000494:pharmacology; D011978:Receptors, Nicotinic / Q000172:deficiency / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D016559:Tacrolimus / Q000494:pharmacology; D064569:alpha7 Nicotinic Acetylcholine Receptor
D002038:Bungarotoxins; D019703:Calcineurin; D065095:Calcineurin Inhibitors; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D018698:Glutamic Acid; D018696:Neuroprotective Agents; D009498:Neurotoxins; D009538:Nicotine; D009543:Nifedipine; D011978:Receptors, Nicotinic; D016559:Tacrolimus; D064569:alpha7 Nicotinic Acetylcholine Receptor; C579166:Chrna7 protein, mouse