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  Director : CHANGEUX, Jean-Pierre (changeux@pasteur.fr)



During 2002, our unity has proposed a 3D structural model of both the active site and the activator calcium binding site of the nicotinic receptor and of its conformational transitions, has demonstrated the importance of transcription factors of the Ets type for the development of the neuromuscular junction, has constructed knock-out alpha6 mice, and shown the importance of the beta2 subunit for the awakening response to a hypoxic stress.



The activity of the " Receptors and Cognition CNRS 2182 " unit is centered on the study of nicotinic acetylcholine receptor, an "allosteric" membrane protein involved in the transduction of chemical neurotransmitter signals into electrical response at the level of the postsynaptic membrane of the neuromuscular junction and of the central nicotinic synapses.

The three main objectives are : (1) identification, at the amino acid level, of the elementary structures engaged in the recognition of nicotinic ligands, in ionic selectivity and transport and their diverse modes of "allosteric" coupling and " up regulation " ; (2) the regulatory mechanisms of gene expression involved in the focal distribution of nicotinic receptors in muscle endplate postsynaptic membrane (in the course of development and in the adult) and (3) the neural processes, in the dendritic vs. axonal compartments of central neurons involved in learning and reward mechanisms associated with nicotine addiction and various brain pathologies.

The methods used to attain the first objective include affinity labeling by specific ligands under rapid mixing conditions, peptide microsequencing, site-directed mutagenesis, stopped-flow with fluorescent ligands in wild type and mutant brain nicotinic receptors, crystallization of the purified protein (or specific fragments) and analysis of the three-dimensional structure. To attain objectives 2 and 3, the most recent advances in recombinant DNA technologies, cloning and sequencing of cDNAs in situ hybridization, promoter analyses, in vivo and in vitro transfection experiments, cloning of transcription factors and conditional homologous recombination in vivo are being exploited, along with cell biology methods such as confocal microscopy.

Ongoing applications of the current work to medicine include : (1) the pharmacology of peripheral and central nicotinic synapses ; (2) the pathology of innervated skeletal muscle and after denervation, myasthenia gravis ; and (3) brain defects resulting from (or associated with) alterations of nicotinic receptors : epilepsy, Alzheimer's and Parkinson's disease, analgesia, aging and nicotine addiction.

Among the original work published in 2002, we emphasize on :

1) the proposition of a computational model of the 3D structure of the extracellular domain of muscular and neuronal nicotinic receptors, including the binding sites for acetylcholine and calcium (Le Novère et coll. 2002).

2) the demonstration by molecular modeling that a different conformation of the active site occurs in the presence of an alpha toxine (basal state) and in the presence of agonist (active or desensitized state) (Fruchart-Gaillard et coll, 2002).

3) the observation of both morphological and molecular composition alterations of the neuro-muscular junction using the in vivo over-expression of an Ets dominant mutant, providing the first demonstration for the role of a specific transcription factor in the synaptic development (de Kerchove d'Exaerde et coll. 2002)

4) the construction of knock-out mice for the alpha6 subunit of the neuronal receptor, and the demonstration that this subunit is involved in the binding of conotoxin M2 (Champtiaux et coll. 2002).

5) the alteration of the awakening response to a hypoxic stress for the beta 2 knock-out mice, providing a plausible model for the sudden death of newborn childs (Cohen et coll. 2002).

5) the long term changes in the liberation of dopamine after a unique and local injection of nicotine within the VTA (Ferrari et coll. 2002), the protective effect of the activation of beta 2 containing neuronal nicotinic receptor against the excitotoxic injury, and the opposite effect for alpha 7 containing receptors (Laudenbach et coll. 2002)

Keywords: nicotinic acetylcholine receptors , allosteric proteins , learning , knockout mice

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  Office staff Researchers Scientific trainees Other personnel
  ADJEMIAN, Martine –changeux@pasteur.fr orjgex@pasteur.fr

GEX, Jacqueline –jgex@pasteur.fr orchangeux@pasteur.fr

BOURGEOIS, Jean-Pierre, CNRS, DR2 :jpbourg@pasteur.fr:

CORRINGER, Pierre-Jean, CNRS, CR1 :pjcorrin@pasteur.fr

DEVILLERS-THIERY, Anne, Sous-Directeur au Collège de France :devill@pasteur.fr

FAURE, Philippe, Pasteur CR2 :phfaure@pasteur.fr

GRANON, Sylvie, Pasteur, CR2 :granon@pasteur.fr

KERSZBERG, Michel, CNRS, DR2 :mkersz@pasteur.fr

KORN, Henri, emeritus professor, Pasteur

LE NOVÈRE, Nicolas, CNRS, CR2:lenov@pasteur.fr

MASKOS, Uwe, Pasteur, CR2 :umaskos@pasteur.fr

NGHIEM, Hoang-Oanh, CNRS, CR1 :honghiem@pasteur.fr

BESSON, Morgane, French PhD student :besson.catieutel@tiscali.fr –norvegian fellowship

CHAMPTIAUX, Nicolas, French PhD student :champtia@pasteur.fr (ATER Collège de France) he attended his thesis on September 24, 2002 and left the lab at the beginning of November 2002

CORDERO-ERAUSQUIN, Matilde, French PhD student:cordero@pasteur.fr (MRT fellowship)

GRAILHE, Régis, French Posdoc :rgrailhe@pasteur.fr (PTR fellowship)

GRUTTER, Thomas, French Postdoc :grutter@pasteur.fr (CEE salary)

HAN, Zhi-Yan, Chinese PhD student:zyhan@pasteur.fr (Sté de Tabacologie fellowship)

LE MAGUERESSE, Corentin, French PhD student:clemag@pasteur.fr (MRT fellowship)

MECHAWAR, Naguib, Canadian postdoc:mechawar@pasteur.fr

PAAS, Yoav, Maître de conférence associé Collège de France :ypaas@pasteur.fr

ROSSI, Francesco Italian Postdoc :frossi@pasteur.fr (France Alzheimer fellowship) (departure March 2003)

SALLETTE, Jérôme, French PhD student:sallette@pasteur.fr (CNRS engineer fellowship)

SUNESEN, Morten, Danish Postdoc : MSUNESEN@pasteur.fr (danish fellowship)

DUFRESNE, Virginie, Engineer, Pasteur (arrived December 3rd 2001)

HUCHET, Monique, Engineer, Collège de France :mohuchet@pasteur.fr

PONS, Engineer, Collège de France :spons@pasteur.fr

SALMON, Anne-Marie, Engineer Pasteur :asalmon@pasteur.fr

LE POUPON, Chantal, Technician Collège de France :cpoupon@pasteur.fr

LE SOURD, Anne-Marie, Technician CNRS :lesourd@pasteur.fr

SOUDANT, Martine, Technician Pasteur

Activity Reports 2002 - Institut Pasteur

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