Gamma aminobutyric acid (GABA) is a naturally occurring amino acid that works as a neurotransmitter in your brain. GABA is considered an inhibitory neurotransmitter because it inhibits certain brain signals and decreases activity in your central nervous system. When released, it binds to neurons at one of two receptors, GABAA and GABAB, and slows their firing rates. GABA is one place for researchers to start looking to understand neuropsychological ailments. Now scientists from the Department of Energy’s SLAC National Accelerator Laboratory, have developed a detailed map of one of GABA’s receptors and have discovered not only the structure, but new details of how it moves from its inactive state to active state.

Their study, “Structural basis of the activation of a metabotropic GABA receptor,” is published in Nature.

The scientists studied GABAB, using cryo-electron microscopy to take detailed pictures of the molecule. Cryo-electron microscopy use beams of electrons rather than light to form images of a sample, and then freezing the sample to preserve it under the harsh conditions in an electron microscope.

“Here we present four cryo-electron microscopy structures of the human full-length GB1–GB2 heterodimer: one structure of its inactive apo state, two intermediate agonist-bound forms, and an active form in which the heterodimer is bound to an agonist and a positive allosteric modulator. The structures reveal substantial differences, which shed light on the complex motions that underlie the unique activation mechanism of GABAB,” wrote the scientists.

The scientists hoped to map the structure of GABAB in both inactive and active states. To their surprise, they found the existence and rough maps of two intermediate states. “We didn’t even know these existed,” stated Cornelius Gati, PhD, an author of the study and structural biologist at the Department of Energy’s SLAC National Accelerator Laboratory.

To observe the active state, the team added two molecules with GABAB and took additional cryo-EM images, which stabilized the GABAB receptor in its active state. “Our results show that agonist binding leads to the closure of the Venus flytrap domain of GB1, triggering a series of transitions, first rearranging and bringing the two transmembrane domains into close contact along transmembrane helix 6 and ultimately inducing conformational rearrangements in the GB2 transmembrane domain via a lever-like mechanism to initiate downstream signaling. This active state is stabilized by a positive allosteric modulator binding at the transmembrane dimerization interface,” the researchers noted.

The activation transition for the GABAB receptor. GABAB comprises two distinct parts, GB1 and GB2. In the first step toward activation, researchers added an agonist, a GABA-like molecule that brings the pieces of GB1 and GB2 that sit outside the cell together. In the second step, the team added a molecule called a positive allosteric modulator, or PAM, which together with the agonist stabilized GABAB in its active form. Credit: Cornelius Gati/SLAC National Accelerator Laboratory.

Being able to see each of those steps along with new details, such as the site where the PAM binds to GABAB, could help researchers design better drugs to treat neuropsychological disease, explained Vadim Cherezov, PhD, a structural biologist at the University of Southern California and co-author of the study.

Their findings about the structure and its transitions between states could help scientists better understand GABA receptors and may eventually lead to better treatments for psychosis and other conditions.

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