Brain activity is responsible for hormones, movement, and many other activities of the entire body. One aspect that piqued the interest of scientists is how a particular protein is responsible for calming the brain and can be used for new drug developments.

Chemical molecules, or neurotransmitters, are messengers that control electrical activity levels within the brain. They interact with proteins across a chemical synapse in between neurons, or nerve cells, opening, and closing portals to control ion flow.

Metabotropic γ-aminobutyric acid receptors are proteins that convert chemical responses within the central nervous system and are responsible for various neuropsychological conditions such as addiction and psychosis. Gamma-aminobutyric acid (GABAB) is a prominent inhibitor neurotransmitter responsible for calming brain activity by blocking impulses.

GABA lowers the number of active signals in the brain to help maintain the balance of other neurotransmitters that energize the brain. The protein has even been added to nutritional supplements for sleep improvement and to promote calm.

Brain Protein Structure

However, a more realistic scenario is that people have imbalanced brain activity where GABA cannot inhibit brain signals, resulting in various health issues such as bipolar disorder, anxiety, muscle spasms, and even epilepsy. Scientists at USC Dornsife College of Letters, Arts and Sciences, and the Bridge Institute at the USC Michelson Center for Convergent Bioscience aimed their study towards figuring out how GABA interacts with a key protein receptor called GABAB. In collaboration with Stanford University, the Stanford Linear Accelerator Center, and the Université de Montpellier in France, they analyzed how GABA affects the shape of GABAB for the development of new drugs.

Using cryo-electron microscopy, or cryo-EM, the team was able to capture how GABAB interacts with GABA which has never been seen before. As a receptor protein, it sits along the membrane of neurons and is made of two subunits. GB1 recognizes GABA while GB2 sends signals from GB1 into the cell.

The cryo-EM images give insight into how GABA interacts with GB1 and causes a ripple effect to the entire protein until the outer membrane opens a way for the GB2 to partially enter the cell. Once inside, GB2 interacts with inside proteins, activating them to control the neuron's activity.

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New Drug Developments

The three-dimensional structural pictures serve as an encouragement to improve neurological disorder therapies, according to Professor Vadim Cherezov, a chemist at USC Dornsife. 'These blueprints can be used to design new therapeutic drugs that could affect different conformational states and thus act more precisely,' he said.

Another significant discovery is the revelation of a critical location on the GABAB where the two subunits meet at the cell membrane when the receptor becomes active. The GB1 and GB2 relationship can now be a target for a developed drug called positive allosteric modulator (PAM)."There are many therapeutic areas in which targeting the GABAB receptor protein could be beneficial; however, such direct interventions may come with significant side-effects," explained Cherezov. 'Developments of PAMs facilitated by our structure images could lead to a new generation of safer drugs targeting this receptor.'

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