New receptor studies

What do certain anaesthetics, sedatives, and drugs for depression, anxiety and epilepsy have in common?

They all act through the same receptor system in the brain, says Prof Michael Parker: the receptors for neurotransmitter gamma-amino butyric acid (GABA). Parker and his colleague at St Vincents Institute of Medical Research, Dr Brett Cromer, have received a $800,000 NHMRC project grant to study the structure of the GABA receptor protein.

Strictly speaking, that should be 'proteins'-- Parker says there are three forms of so-called GABA receptors in the brain, called GABA A, GABA B and GABA Rho.

Parker's team is focusing on the A and Rho receptors. These two receptor types share only 20 to 30 per cent of their DNA code, yet their proteins are structurally very similar -- both are GABA-gated ion channels which influence neural activity by regulating the flux of chloride ions through nerve membranes.

The team already has a preliminary model of the external domain of the receptor, which interacts with GABA and the various drugs used to induce anaesthesia, or treat brain disorders and mental illness.

The St Vincents team will use its NHMRC project grant to investigate the multiple binding sites that GABA receptors offer for these diverse molecules.

"It's a marvellous protein to study," says Parker.

The NHMRC grant is for five years, and Parker says the team plans to take it all the way from producing crystals of the GABA receptor protein and analysing its structure, to investigating the molecular genetics involved.

By determining how mutations or subtle variations in the DNA of the gene modify the structure of the GABA receptor, the team hopes to understand why certain individuals are more susceptible to depression, anxiety or epilepsy.

Such structural details could allow chemists to design potent new drugs to treat these disorders with minimal side-effects.