Investigation of the function and development of the pharmacology of heteromeric kainate receptors
This PhD project will focus on the discovery, development and in vitro pharmacological characterization of novel ligands for the kainate type of ionotropic glutamate receptors (GluK1-5) as well as on the characterization of existing ligands at heteromeric recombinant and native kainate receptors (KAR). This project will be carried out primarily within the Dept. of Pharmacology and Pharmacotherapy and the Dept. of Medicinal Chemistry at the Faculty of Pharmaceutical Sciences, University of Copenhagen. This project will be an integrated part of the University of Copenhagen GluTarget programme of excellence (www.glutarget.ku.dk).
Hypothesis: Knowledge of the pharmacology of heteromeric kainate receptors (KAR) will facilitate understanding of KAR role(s) in normal and pathological brain function. The development of subtype-selective drugs is a prerequisite to the understanding of KAR function.
Background: The ionotropic glutamate receptors (iGluRs) are tetrameric, ligand-gated ion channels and have been divided into three different classes on the basis of protein sequence identity and ligand selectivity: AMPA, kainic acid (KA) and NMDA receptors. iGluRs couple the energy of agonist binding to the opening of a transmembrane ion pore, allowing influx of Na+, K+ or Ca2+ ions and thereby cause membrane depolarization and neuronal excitation to produce an electrical signal from the chemical stimulus.
iGluRs of the kainate receptor (KAR) class exist in brain mainly as heteromeric receptor complexes (as a so-called dimer of dimers). KARs are believed to be involved in a wide range of normal physiological processes (e.g. memory and learning) as well as pathophysiological processes (e.g. neurodegeneration, schizophrenia). The development of KAR subtype-selective ligands (agonists, partial agonists, antagonists, and allosteric modulators) is essential to the clarification of the roles of the different KAR subtypes in these normal and disease processes. Despite extensive efforts by many research groups only a few truly subtype-selective ligands have been developed. While the pharmacology of homomeric cloned KARs has been/is being studied extensively, the pharmacological properties of heteromeric receptor complexes are much less well characterised. Compounds exhibiting novel or selective activity at heteromeric KARs therefore have relevance to the overall understanding of the physiological role of KARs as well as providing potential lead compounds in the drug discovery process.
The development, design and synthesis of KAR ligands have been an ongoing concern here at FARMA for many years. Using recent information obtained from biostructural studies of KAR-ligand binding, the design and synthesis of novel ligands is currently underway. This PhD project will therefore provide a functional, pharmacological component to supplement the synthetic and biostructural studies of new ligands.
Methods and Techniques: The proposed project will involve: i) molecular biological manipulations of cloned KAR, ii) creation of stable cell lines expressing KAR, iii) development of a fluorescence-based ligand screening assay, iv) two-electrode voltage clamp (TEVC) electrophysiological characterisation of recombinant rat KAR expressed in Xenopus oocytes, v) patch clamp characterisation of KAR in cell lines and neuronal cultures.
Applicant Qualifications: Due to stipend funding preconditions, graduates of the University of Copenhagen are not eligible for this stipend. The ideal applicant should possess a keen interest in, and experience within, the area of neuropharmacology. Preference will be given to applicants having practical expertise in the techniques relevant to the project: electrophysiology, molecular biology, cell culture. The GluTarget programme of excellence consists of researchers having a wide range of expertise, ranging from: molecular modelling, protein crystallography, medicinal chemistry, chemical biology, molecular pharmacology and in vivo pharmacology. The selected candidate will be expected to be able to interact within this multi-disciplinary research environment as well as to provide the personal initiative to drive the project forward.
For further project information, please contact the project main supervisor:
Darryl Pickering, Ph.D., assoc. prof.
Dept. of Pharmacology and Pharmacotherapy
Faculty of Pharmaceutical Sciences
University of Copenhagen
Universitetsparken 2
2100 Copenhagen
Denmark
email: picker(at)farma.ku.dk
Note: Applications should not be sent directly to the main supervisor but must be submitted to the Faculty administration for consideration.
