Ionotropic receptors for inhibitory amino acids (GABA, glycine) with emphasis on the relation to epilepsy

We study aspects of pharmacodynamics and inhibitory neurotransmission. A current focus area is the kinetics of ligand-receptor interaction at GABA_A receptors.

1. Pharmacodynamics: Most biological processes take place under non-equilibrium conditions where kinetic considerations are critical. This also applies to many drug-receptor interactions and derived processes, however, pharmacodynamic studies often do not take kinetic aspects into account. This limits the amount of information that can be extracted from the experiments and may lead to erroneous conclusions. For fast, desensitizing receptors, like the GABA_A receptor, two matters are of special importance. 1) The experimental time-concentration profiles of ligands need to be accounted for and, if possible, be physiologically relevant. 2) The right measures must be used to extract relevant information from the pharmacological responses. Using patch-clamp electrophysiology with variable rates of ligand application and different methods of response measurements in combination with kinetic computer modelling, we aim to optimize experimental design and quantification methods in order to increase information yield and validity of conclusions.
2. Neurotransmission: We have proposed that the inherent differences in time-concentration profiles of the neurotransmitters at the synaptic receptors, mediating phasic neurotransmission, and at the extrasynaptic receptors, mediating tonic neurotransmission, respectively, can be used as a tool to improve drug selectivity (receptor selectivity by kinetics). This principle is not accounted for by the conventional methods to obtain and estimate drug selectivity. Currently we aim to validate the principle with application to GABAergic neurotransmission. We use GABA_A receptor antagonists with different kinetic properties as determined in experiments with recombinant receptor subtypes. The antagonists are evaluated with a combination of patch-clamp electrophysiology in brain slices and computer modelling of kinetics of GABA time-concentration profiles and receptor interaction.

Generel fysiologi. Neurofysiologi og -farmakologi. Farmakodynamik. Ionkanal-kinetik