Allosteric regulation of neuronal acetylcholine nicotinic receptor: implication for short-term plasticity, brain pathology and neuropharmacology

• Research unit: EU RFP
• Project number: 96.0295-1

Key words (English)

Brain; neuronal nicotinic acetylcholine receptor; neurological disorder; epilepsy; pharmaxology

Alternative project number (English)

EU project number: BIO4CT960236

Research programs (English)

EU-programme: 4. Frame Research Programme - 4.1 Biotechnology

Short description (English)

See abstract

Partners and International Organizations (English)

Institut Pasteur, Universität München, Karolinska Institut, Glaxo Genève

Abstract (English)

The main objective of this project is to understand the properties of the neuronal nicotinic acetyicholine receptors and their implication in normal or pathological brain functions.

Major achievement obtained during this year concern: 1) the identification of a fast synaptic transmission mediated by nicotinic acetylcholine receptor in the hippocampus, ii) the characterisation of the pharmacological profile of receptors that are spontaneously altered in a genetically transmissible form of epilepsy, iii) studies of the physiological and pharmacological properties of new epibatidine derivatives that are designed for PET imaging, iv) analysis of the molecular determinant of the desensitisation properties conferred by the b subunit, v) the identification of the pharmacological profile of native receptors in rat brain slices.

Structure function studies of ligand gated channels have initially revealed the importance of key amino add residues on the properties of these integral proteins. In the most recent studies we were able to demonstrate the role of the N-terminal domain of the b subunit on the desensitization properties of a3 containing receptors. The relevance of these studies was highlighted by the discovery of genetically transmissible disorders and their characterisation at the molecular level. Combination of these new approaches allowed to characterise receptor function at the amino acid level and to determine the pharmacogenomic profile of a given receptor subtype. Paralleled with clinical observations these data provide a first set of evidences for the higher sensitivity of certain patients to a given anticonvulsive drug. Additional elements regarding the contribution of nicotinic receptor on the brain function have been obtained from rat brain studies and it becomes more and more important to identify the receptor distribution and function, both in normal and pathological conditions. Availability of PET ligands will allow the investigation in a non-invasive manner receptor distribution in human and their alteration in neuropathological condition.

References in databases (English)

Swiss Database: Euro-DB of the
State Secretariat for Education and Research
Hallwylstrasse 4
CH-3003 Berne, Switzerland
Tel. [phone]
Swiss Project-Number: 96.0295-1