Neuroprotection by nicotine in mouse primary cortical cultures involves activation of calcineurin and L-type calcium channel inactivation
Open accessAbstract
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.
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Activation of nicotinic acetylcholine receptors can decrease subsequent stimulation of calcium entry into cortical neurons in response to glutamate.
“In addition, activation of nAChRs can also decrease subsequent stimulation of calcium entry into cortical neurons in response to glutamate (Stevens et al., 2003).”
From Acetylcholine as a Neuromodulator: Cholinergic Signaling Shapes Nervous System Function and Behavior (2012) · cites this paper as Stevens et al., 2003
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- Authors
- Stevens, T. R., Krueger, S. R., Fitzsimonds, R. M., & Picciotto, M. R.
- Affiliations
- Yale University (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2003-11-05
- Volume
- 23
- Issue
- 31
- Pages
- 10093-10099
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6740855
- OpenAlex
- W2141567624
- Cited by
- 119
- References
- 50
- Citations by year
- 2026: 3 · 2024: 1 · 2023: 3 · 2022: 3 · 2021: 3 · 2020: 2 · 2019: 2 · 2018: 8 · 2017: 4 · 2016: 4 · 2015: 3 · 2014: 6 · 2013: 6 · 2012: 7
- FWCI
- 2.65
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Burroughs Wellcome Fund
- Alzheimer's Association
- National Institutes of Health (DA14241, DA10455, DA00436)
- National Institute of Mental Health (R01MH059800, MH-59800)
- National Institute on Drug Abuse (DA14241, K02DA000436, DA 10455, R01DA014241, R29DA010455, R01DA010455, DA 00436)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
- Keywords
- nicotine, neuroprotection, glutamate excitotoxicity, calcineurin, L-type calcium channels, nicotinic acetylcholine receptors, beta2 subunit, alpha7 subunit, intracellular calcium, calcium influx, cortical neurons, nifedipine, FK506, cyclosporine, alpha-bungarotoxin
- MeSH terms
- Animals, Bungarotoxins, Calcium Channel Blockers, Cells, Cultured, Cerebral Cortex, Neurons, Neurotoxins, Nicotine, Nifedipine, Receptors, Nicotinic, Tacrolimus, Mice, Knockout, Neuroprotective Agents, Glutamic Acid, Calcineurin, Calcium Channels, L-Type, Mice, alpha7 Nicotinic Acetylcholine Receptor, Calcineurin Inhibitors
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