title: Neuroprotection of midbrain dopamine neurons by nicotine is gated by cytoplasmic Ca2+.
abstract: Epidemiological and experimental evidence indicates that nicotine is protective for Parkinson disease vulnerable dopamine neurons, but the underlying mechanism of this effect remains only partly characterized. To address this question, we established rat midbrain cultures maintained in experimental conditions that favor the selective and spontaneous loss of dopamine neurons. We report here that nicotine afforded neuroprotection to dopamine neurons (EC(50)=0.32 μM) but only in a situation where cytosolic Ca(2+) (Ca(2+)(cyt)) was slightly and chronically elevated above control levels by concurrent depolarizing treatments. By a pharmacological approach, we demonstrated that the rise in Ca(2+)(cyt) was necessary to sensitize dopamine neurons to the action of nicotine through a mechanism involving α-bungarotoxin-sensitive (presumably α7) nicotinic acetylcholine receptors (nAChRs) and secondarily T-type voltage-gated calcium channels. Confirming the role played by α7 nAChRs in this effect, nicotine had no protective action in midbrain cultures prepared from genetically engineered mice lacking this receptor subtype. Signaling studies revealed that Ca(2+)(cyt) elevations evoked by nicotine and concomitant depolarizing treatments served to activate a survival pathway involving the calcium effector protein calmodulin and phosphatidylinositol 3-kinase. Collectively, our data support the idea that the protective action of nicotine for dopamine neurons is activity-dependent and gated by Ca(2+)(cyt).
authors.affiliation: Université Pierre et Marie Curie-Paris 6, Centre de Recherche de l'Institut du Cerveau et de la Moelle Epinière, Unité Mixte de Recherche-S975, Paris, France.
authors.forename: Damien
authors.initials: D
authors.lastname: Toulorge
authors.forename: Serge
authors.initials: S
authors.lastname: Guerreiro
authors.forename: Audrey
authors.initials: A
authors.lastname: Hild
authors.forename: Uwe
authors.initials: U
authors.lastname: Maskos
authors.forename: Etienne C
authors.initials: EC
authors.lastname: Hirsch
authors.forename: Patrick P
authors.initials: PP
authors.lastname: Michel
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020747:Calcium Channels, T-Type / Q000378:metabolism; D002147:Calmodulin / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D003593:Cytoplasm / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000378:metabolism; D015640:Ion Channel Gating / Q000187:drug effects; D008636:Mesencephalon / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D051379:Mice; D008959:Models, Neurological; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009538:Nicotine / Q000494:pharmacology*; D026902:Potassium Channel Blockers / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D011978:Receptors, Nicotinic / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D019789:Tetraethylammonium / Q000494:pharmacology; D046509:Tissue Culture Techniques; D064569:alpha7 Nicotinic Acetylcholine Receptor
chemical_list: D020747:Calcium Channels, T-Type; D002147:Calmodulin; C579166:Chrna7 protein, mouse; C579165:Chrna7 protein, rat; D051100:Glial Cell Line-Derived Neurotrophic Factor; D018696:Neuroprotective Agents; D026902:Potassium Channel Blockers; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; D019789:Tetraethylammonium; D009538:Nicotine; D051057:Proto-Oncogene Proteins c-akt; D002118:Calcium; D004298:Dopamine