Image of the Week: GABA-A receptor

This image is based on the first X-ray structure of a GABA_A receptor, the human GABA_A beta3, recently published in Nature by Dr Paul Miller and Dr Radu Aricescu from the Wellcome Trust Centre for Human Genetics, University of Oxford. The receptor is viewed from the outside of a neuronal cell. Its five subunits are coloured, and a patch of lipids from the surrounding neuronal membrane is modelled as grey spheres.

GABA_A receptors play vital roles in neurological disorders such as epilepsy, insomnia and anxiety, and mediate the action of antidepressants, general anaesthetics and alcohol.

The neurotransmitter gamma-aminobutyric acid, known as GABA, dampens activity in neurons by binding to GABA_A receptors in the nerve cell membrane. This means that GABA_A receptors are the brakes of the brain: they spread calm and regulate excitement. When these regulators fail, brain activity increases, which can lead to a range of debilitating illnesses that affect tens of millions of people worldwide.

Researchers used their understanding from many years of research into various forms of human GABA_A receptors to construct one that, unusually, they were able to crystallise successfully. They then used the powerful X-ray beam at the Diamond Light Source to obtain diffraction data from the crystal.

Their findings reveal a large structure consisting of five protein subunits that cross from one side of the cell membrane to the other and create a gated channel. Visualising the receptor at high resolution made it possible to identify the areas on the molecule where GABA and other inhibitory molecules bind. This helps to explain how that binding opens the channel so that chloride ions can enter the cell, making it less sensitive to excitatory inputs.

“Human GABA_A receptor subunits are encoded by 19 different genes” says Dr Aricescu. “Although the structure we report can be considered ground-breaking, we have only scratched the surface of an enormously complex system. But we are extremely optimistic because most of the technologies we developed along the way should be transferable to other members of the same receptor family and facilitate rapid progress of the field.”

Image credit: X-ray crystal structure of the neurotransmitter receptor GABA_A – Radu Aricescu, Paul Miller and Phillip Stansfeld

Reference: Miller P & Aricescu AR, Crystal structure of a human GABA_A receptor, Nature (2014) doi:10.1038/nature13293