Ass. Prof. Priv. Doz. Dr. Margot Ernst

GABAA receptors functional and pharmacological studies

Background / Objective: GABA_A receptors are a large family of GABA gated ion channels serving many physiological functions. Allosteric modulators of these receptors (e.g. benzodiazepines and sedative anesthetics) are among the staples of pharmacotherapy, and yet the mechanisms of channel function and pharmacology are far from fully understood. Each receptor subunit contains three protein domains. The intracellular domain (ICD) is the least conserved one, and very little is known about its function. ICD deletion leaves receptors functional, but alters a range of functions. Two patient derived GABRa1 mutations in the ICD (which will also be studied in the Novarino lab) will be at the core of this project, where it will be interesting to get an integrated picture of the molecular phenotype (this work) and a potential phenotype in a brain organoid (Novarino lab). Additional lines of work deal with the pharmacology of wild type receptors and subserve development of novel pharmacological tools for research (photo- activated allosteric modulators) and brain imaging (isotope labelled high affinity ligands).

Methods: Wild type receptors and receptors with altered ICDs will be expressed in recombinant systems (mainly Xenopus oocytes). Receptor function and ligand effects will be studied with the two electrode voltage clamp technique and other auxiliary methods. Computational modelling will provide mechanistic and structural insight and guide further mutational work to validate predictions. Lab rotations will add methods to the portfolio.

Networking / Collaborations: Collaborations with synthetic chemists (Mihovilovic, Maulide) and computational groups (González, Ecker, Weinzinger) and with the IST (Novarino, possibly also Danzl) provide strong synergy.

Expected results: This study will deliver data on functional coupling between domains, and aim to generate mechanistic insights as well. In the different collaborations we make contributions to the development of research tools as well as diagnostically or therapeutically useful small molecules.