Sci Signaling｜Jianfeng Liu's team reveals that GABAB receptors activate G13 protein pathways to promote neuroprotection

EditorZyme G-protein-coupled receptors (GPCRs) are the largest family of membrane receptor proteins in the human body.
They play an important role in cell signal transduction and are closely related to various diseases
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It is known that GPCR activates the MAPK signaling pathway through different G proteins or β-arrestins, and then regulates a series of physiological functions.
It is an important target for drug research and development.
More than 30% of marketed drugs are developed with GPCR targets
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Type B γ-aminobutyric acid receptors (GABAB receptors) belong to the C family of GPCRs.
They are widely present in the presynaptic and postsynaptic membranes.
They mediate long-term inhibitory synaptic activity and regulate different functions.

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Studies have reported that baclofen, a specific agonist of GABAB receptors, can be used to relieve convulsions and alcohol addiction
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In addition, GABAB receptor dysfunction is associated with many neurological and mental diseases such as epilepsy, depression, anxiety, mental retardation, and Alzheimer's disease
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All these indicate that the GABAB receptor is a very important and promising drug target
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Professor Liu Jianfeng's research group has been engaged in the study of the structure and function of GABAB receptors for a long time, and has conducted systematic and in-depth research on the structure and activation of the GABAB receptor and the binding mode, function and signal pathway of G protein
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Since 2019, the research team has published articles in Nature, Nature Communication, Cell research and other journals to clarify the activation process of GABAB receptors (Nature Communication, 2019; Cell Research, 2020) and the unique mode of binding to Gi protein (Nature, 2021 )
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The binding of Gi protein to GABAB receptor is a very flexible weak interaction
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Whether the GABAB receptor can couple to other G proteins besides Gi/o is still unclear
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On October 19, 2021, Science Signaling published online the latest scientific research results of Professor Liu Jianfeng’s team from the School of Life Sciences of Huazhong University of Science and Technology entitled The GABAB receptor mediates neuroprotection by coupling to G13, revealing the mechanism by which GABAB receptors activate G13 protein pathways to promote neuroprotection
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Professor Liu Jianfeng’s research group continued the previous research results.
In the primary cultured neurons, it was further discovered that GABAB receptors can not only couple with Gi/o, but also couple and activate G13, and exert synaptic function regulation through the G13/JNK signaling pathway.
And neuroprotection
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This allows us to better understand the functional diversity of GABAB receptors in the brain, and provides new ideas for the development of drugs targeting GABAB receptors
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GABAB receptors can activate different MAPK signaling pathways by coupling different G proteins, and at the same time can play a neuroprotective effect through the synergy of the G13/Rac1/JNK signaling pathway and the Gi/o/IGF1R/Akt signaling pathway
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This suggests that for some specific GPCRs, two different signal pathways are needed to regulate their functions together, which has a good guiding significance for us to better understand the functional diversity of GPCRs
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Figure: Schematic diagram of GABAB receptor activation downstream of different G protein signaling pathways.
This work is another important achievement of Professor Liu Jianfeng's group in the function and activation mechanism of GABAB receptors
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It was completed by PhD students Wang Yunyun and Gai Siyu from the School of Life Sciences, the Key Laboratory of Biophysics of the Education Department, and the International Joint Research Center for Perceptual Biotechnology of the Ministry of Science and Technology under the joint guidance of Professor Liu Jianfeng and Lecturer Xu Chanjuan
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Article link: https://pubmed.
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