Structural Basis of GABAB Receptor Activation during Evolution.
Guofei Hou1,2, Shenglan Zhang2, Cangsong Shen1,2,3
1Cellular Signaling laboratory, International Research Center for Sensory Biology and Technology of MOST, Key Laboratory of Molecular Biophysics of MOE, School of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, China.
Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|July 12, 2025
Summary
The study reveals that the Drosophila GABAB receptor
Area of Science:
- Neuroscience
- Structural Biology
- Biochemistry
Background:
- GABAB receptors are essential Class C G protein-coupled receptors (GPCRs) mediating inhibitory neurotransmission via GABA.
- These receptors form obligate heterodimers of GB1 and GB2 subunits, crucial for their function.
- Understanding the evolutionary conservation of GABAB receptor activation mechanisms is vital.
Purpose of the Study:
- To elucidate the activation mechanism of the Drosophila GABAB receptor using structural biology.
- To compare the activation mechanism with its human homolog, investigating evolutionary conservation.
- To identify structural differences influencing receptor activity and allosteric modulation.
Main Methods:
- Cryogenic electron microscopy (cryo-EM) was employed to determine high-resolution structures.
- Structures were obtained for the Drosophila GABAB receptor in inactive (antagonist-bound) and active (GABA-bound) states.
- Complex structures with the Gi protein were analyzed to understand G protein coupling.
Main Results:
- Drosophila GABAB receptor displays asymmetric activation, similar to its human counterpart.
- A larger inactive interface in the Drosophila receptor prevents constitutive activity.
- Key residues for positive allosteric modulator activity in humans are not conserved in Drosophila; specific regions of GB2 are critical for G protein coupling.
Conclusions:
- Evolutionary variations in GABAB receptor structure impact activation and allosteric modulation.
- The findings provide a comprehensive understanding of GABAB receptor activation mechanisms.
- Insights gained can guide the development of novel therapeutics and insecticides targeting GABAB receptors.
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