Structural basis of GABA reuptake inhibition
Zenia Motiwala1,2, Nanda Gowtham Aduri1,2, Hamidreza Shaye1,3,4
1Bridge Institute, USC Michelson Center for Convergent Biosciences, University of Southern California, Los Angeles, CA, USA.
Nature
|June 8, 2022
Summary
The structure of human γ-aminobutyric acid transporter 1 (GAT1) bound to tiagabine reveals how this anticonvulsant drug blocks GABA uptake. This provides insights into GAT1 inhibition and aids the design of new neuromodulators.
Area of Science:
- Neuroscience
- Structural Biology
- Pharmacology
Background:
- γ-Aminobutyric acid (GABA) transporter 1 (GAT1) regulates neuronal excitation by clearing GABA from the synaptic cleft.
- Inhibiting GABA reuptake is a strategy for treating neurological disorders like epilepsy.
Purpose of the Study:
- To determine the cryo-electron microscopy structure of human GAT1 in complex with the inhibitor tiagabine.
- To elucidate the mechanism of tiagabine's mixed-type inhibition of GAT1.
Main Methods:
- Cryo-electron microscopy (cryo-EM) of full-length human GAT1.
- Complex formation with the inhibitor tiagabine.
- Structural analysis of the GAT1-tiagabine complex.
Main Results:
- The structure reveals tiagabine locks GAT1 in an inward-open conformation, blocking GABA release.
- Tiagabine suppresses neurotransmitter uptake by inhibiting GAT1.
- The findings support a two-step inhibition mechanism involving outward-open and inward-open conformations.
Conclusions:
- The GAT1-tiagabine structure provides crucial insights into GAT1 biology and pharmacology.
- This structure serves as a blueprint for designing novel neuromodulators.
- The study advances the capabilities of cryo-EM for challenging membrane proteins.
More Related Videos
Related Concept Videos
01:18Antiepileptic Drugs: GABAergic Pathway Potentiators
689
γ-aminobutyric acid or GABA, plays a pivotal role as an inhibitory neurotransmitter in the brain. GABA pathway potentiators, also known as GABAergic drugs, are a class of pharmaceutical agents designed to enhance the functioning of the GABAergic system. These medications primarily treat epilepsy, a neurological disorder characterized by recurrent seizures.
The key GABA pathway potentiators used in epilepsy management are as follows.
Benzodiazepines are a well-known class of drugs used for...
The key GABA pathway potentiators used in epilepsy management are as follows.
Benzodiazepines are a well-known class of drugs used for...
689
01:30Ligand-Gated Ion Channel Receptor: Gating Mechanism
2.7K
Ligand-gated ion channels are transmembrane proteins that play a vital role in intercellular communication and functions of the nervous system. They allow the influx of ions across the membrane once the neurotransmitter binds, allowing the subsequent transmission of electrical excitation across the neurons. Other ligand-gated ion channels, like the γ-aminobutyric acid (GABA) receptor, permit anions like chloride into the cells on the binding of the GABA molecule. Their entry into the cell...
2.7K
01:12GPCR Desensitization
6.6K
G protein-coupled receptor (GPCR) signaling plays a crucial role in cell functioning. GPCR desensitization is an equally essential process. It allows cells to respond to changing environments and regain sensitivity to new stimuli while preventing unnecessary stimulation when no longer needed. Prolonged exposure to stimuli leads to GPCR desensitization. It involves blocking the receptors from binding and activating additional G proteins. This inhibits activation of downstream effectors, thereby...
6.6K
01:29Excitatory and Inhibitory Effects of Neurotransmitters
10.9K
When an action potential reaches the presynaptic axon terminal, it releases neurotransmitters from the neuron into the synaptic cleft at a chemical synapse. The released neurotransmitter can be excitatory or inhibitory. The critical criteria commonly used to determine whether a molecule is a neurotransmitter at a chemical synapse are the molecule's presence in the presynaptic neuron. Second, its release is in response to strong presynaptic depolarization. And lastly, the presence of...
10.9K
01:14CNS Depressants: Barbiturates and Benzodiazepines
486
CNS depressants include drugs from the category of barbiturates and benzodiazepines. They are valuable medications for managing anxiety disorders and insomnia. Barbiturates, once used to induce and maintain sleep, have been replaced mainly by benzodiazepines due to barbiturate's toxicity, tolerance, and overdose risks. They interact with GABAA receptors, leading to sedation at low doses and potentially coma and death at higher doses. Phenobarbital, a long-acting barbiturate, possesses...
486
01:26Neurochemical Transmission: Sites of Drug Action
2.7K
Neurochemical transmission, the conduction of electrical impulses between neurons mediated by neurotransmitters, plays a vital role in various physiological processes. Autonomic drugs exert their effects by modulating neurotransmission within the autonomic nervous system. For instance, drugs such as hemicholinium block the precursor uptake necessary for synthesizing acetylcholine, an essential autonomic neurotransmitter. Following synthesis, neurotransmitters are stored in vesicles. Metyrosine...
2.7K