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Cryo-EM, a powerful microscopy technique, was used by researchers to decode the molecular architecture of a transporter protein that controls the movement of a key neurotransmitter.
The findings were published in the journal, 'Nature Structural & Molecular Biology.' Neurotransmitters are chemical signals that allow neurons or nerve cells to communicate with one another. Each neurotransmitter can activate specific groups of proteins known as receptors, which can either excite or inhibit neural communication. For neural circuitry to maintain normal structure and function, a healthy balance of excitation and inhibition is required. Seizures, anxiety, and schizophrenia can all result from excitatory or inhibitory input imbalances. GABA, an inhibitory neurotransmitter, balances out the excitatory inputs from glutamate, another neurotransmitter. GABA receptor proteins interact with GABA released from preceding neurons in the circuit to modulate GABA-driven signalling at neural synapses (junctions between neurons). For subsequent release events to occur, excess GABA released into neural synapses must be recycled into neurons and surrounding glial cells. The primary molecules involved in this step are GABA transporters (GATs), which use sodium and chloride ions to move excess GABA back into neurons. As a result, GATs are critical molecules that orchestrate GABA signalling and function. As a result, they are an important target for the treatment of conditions such as seizures. The current study, led by Aravind Penmatsa, Associate Professor in the Molecular Biophysics Unit (MBU), IISc, deciphers the molecular architecture of GAT using cryo-electron microscopy. The technique has the capacity to image and reconstruct the structure of biomolecules that are more than a million times smaller than the width of a human hair. The researchers purified GAT and used a novel approach to create an antibody site on this molecule. Antibodies help increase the mass of proteins and facilitate improved imaging through cryo-EM. The team observed that the GAT structure was facing the cytosol - the inside of the cell - and was bound to a GABA molecule, sodium and chloride ions. This binding is one of many key steps in the GABA transport cycle; deciphering it can provide vital insights into the mechanisms of GABA recognition and release into neurons. The availability of high-resolution GAT structures is crucial for developing specific blockers of GABA uptake to treat epilepsies. It would also aid in studying how drugs prescribed to block GABA uptake interact with GATs. (ANI)
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