title: Human polymorphisms in nicotinic receptors: a functional analysis in iPS-derived dopaminergic neurons.
abstract: Tobacco smoking is a public health problem, with ∼5 million deaths per year, representing a heavy burden for many countries. No effective therapeutic strategies are currently available for nicotine addiction, and it is therefore crucial to understand the etiological and pathophysiological factors contributing to this addiction. The neuronal α5 nicotinic acetylcholine receptor (nAChR) subunit is critically involved in nicotine dependence. In particular, the human polymorphism α5D398N corresponds to the strongest correlation with nicotine dependence risk found to date in occidental populations, according to meta-analysis of genome-wide association studies. To understand the specific contribution of this subunit in the context of nicotine addiction, an efficient screening system for native human nAChRs is needed. We have differentiated human induced pluripotent stem (iPS) cells into midbrain dopaminergic (DA) neurons and obtained a comprehensive characterization of these neurons by quantitative RT-PCR. The functional properties of nAChRs expressed in these human DA neurons, with or without the polymorphism in the α5 subunit, were studied with the patch-clamp electrophysiological technique. Our results in human DA neurons carrying the polymorphism in the α5 subunit showed an increase in EC50, indicating that, in the presence of the polymorphism, more nicotine or acetylcholine chloride is necessary to obtain the same effect. This human cell culturing system can now be used in drug discovery approaches to screen for compounds that interact specifically with human native and polymorphic nAChRs.-Deflorio, C., Blanchard, S., Carisì, M. C., Bohl, D., Maskos, U. Human polymorphisms in nicotinic receptors: a functional analysis in iPS-derived dopaminergic neurons.
authors.affiliation: Unité Neurobiologie Intégrative des Systèmes Cholinergiques, Département de Neuroscience, Institut Pasteur, Paris, France.
authors.forename: Cristina
authors.initials: C
authors.lastname: Deflorio
authors.affiliation: Unité Neurobiologie Intégrative des Systèmes Cholinergiques, Département de Neuroscience, Institut Pasteur, Paris, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Blanchard
authors.affiliation: Unité Neurobiologie Intégrative des Systèmes Cholinergiques, Département de Neuroscience, Institut Pasteur, Paris, France.
authors.forename: Maria Carla
authors.initials: MC
authors.lastname: Carisì
authors.affiliation: Unité Neurobiologie Intégrative des Systèmes Cholinergiques, Département de Neuroscience, Institut Pasteur, Paris, France.|Institut du Cerveau et de la Moelle Epinière, INSERM Unité 1127, CNRS, UMR 7225, Université Pierre et Marie Curie, Paris, France.
authors.forename: Delphine
authors.initials: D
authors.lastname: Bohl
authors.affiliation: Unité Neurobiologie Intégrative des Systèmes Cholinergiques, Département de Neuroscience, Institut Pasteur, Paris, France; umaskos@pasteur.fr.|Centre National de la Recherche Scientifique (CNRS), Unité Mixte de Recherche (UMR) 3731, Institut Pasteur, Paris, France; and.
authors.forename: Uwe
authors.initials: U
authors.lastname: Maskos
mesh_terms: D001921:Brain / Q000166:cytology; D002460:Cell Line; D059290:Dopaminergic Neurons / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism*; D011110:Polymorphism, Genetic; D011978:Receptors, Nicotinic / Q000235:genetics / Q000378:metabolism*
chemical_list: D011978:Receptors, Nicotinic
keywords: GWAS; electrophysiology; screening system; smoking; stem cells