Neuroprotection by nicotine in mouse primary cortical cultures involves activation of calcineurin and L-type calcium channel inactivation

J Neurosci. 2003 Nov 5;23(31):10093-9. doi: 10.1523/JNEUROSCI.23-31-10093.2003.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Bungarotoxins / pharmacology
  • Calcineurin / metabolism*
  • Calcineurin Inhibitors
  • Calcium Channel Blockers / pharmacology
  • Calcium Channels, L-Type / drug effects*
  • Calcium Channels, L-Type / metabolism
  • Cells, Cultured
  • Cerebral Cortex / cytology
  • Cerebral Cortex / drug effects*
  • Cerebral Cortex / metabolism
  • Glutamic Acid / toxicity
  • Mice
  • Mice, Knockout
  • Neurons / drug effects*
  • Neurons / metabolism
  • Neuroprotective Agents / pharmacology*
  • Neurotoxins / toxicity
  • Nicotine / pharmacology*
  • Nifedipine / pharmacology
  • Receptors, Nicotinic / deficiency
  • Receptors, Nicotinic / drug effects
  • Receptors, Nicotinic / genetics
  • Receptors, Nicotinic / metabolism
  • Tacrolimus / pharmacology
  • alpha7 Nicotinic Acetylcholine Receptor

Substances

  • Bungarotoxins
  • Calcineurin Inhibitors
  • Calcium Channel Blockers
  • Calcium Channels, L-Type
  • Chrna7 protein, mouse
  • Neuroprotective Agents
  • Neurotoxins
  • Receptors, Nicotinic
  • alpha7 Nicotinic Acetylcholine Receptor
  • nicotinic receptor beta2
  • Glutamic Acid
  • Nicotine
  • Calcineurin
  • Nifedipine
  • Tacrolimus