GABA_B receptors are the principal inhibitory G-protein coupled receptors in the brain and hold considerable promise as therapeutic targets for the treatment of neurological and psychiatric disorders, including anxiety, depression, addiction, epilepsy, and chronic pain. They are composed of two different subunits, GABA_B1 and GABA_B2.

For a long time, it was believed that the different responses observed in the brain in response to GABA_B receptor activation reflected the presence of different GABA_B receptor subtypes. However, we now know that the only molecular diversity in the GABA_B system arises from the two isoforms of the GABA_B1 subunit: GABA_B1a and GABA_B1b. Surprisingly, these two isoforms have very similar pharmacological and biophysical properties in vitro, which makes it difficult to explain the pharmacological and kinetic differences of native GABA_B responses.

A family of four sequence-related proteins were recently found to interact with the receptor and to modify the GABA_B-mediated response when coexpressed with the receptor in vitro. The present project aims at elucidating the molecular events underlying the kinetics changes that these auxiliary proteins impose on the GABA_B receptor response. Assays based on Fluorescence Resonance Energy Transfer (FRET) will be used to investigate whether these proteins interact with different components of the GABA_B-mediated signalling cascade, and how these interactions are modulated upon receptor activation.

These experiments will allow us to provide a mechanistic explanation of how these proteins modify kinetic and pharmacological properties of GABA_B responses and contribute to the functional heterogeneity observed with native GABA_B responses. Identification of the function of these proteins will spark drug discovery efforts, as this provides an opportunity for a more selective interference with the GABA_B receptor system.