New Modes of GPCR Signalling

ABSTRACT
Activation Mechanism of GABAB Receptor
Chanjuan Xu, Wenhua Zhang, Xin Lin, Ming Jiang, Haijun Tu, Siluo Huang, Jianfeng
Liu*
Sino-France Laboratory for Drug Screening, Key Laboratory of Molecular Biophysics of
Ministry of Education, School of Life Science and Technology, Huazhong University of
Science and Technology, WuHan, 430074
Class-C G-protein coupled receptors (GPCRs) represent a distant group among the large
family of GPCRs. This class includes the receptors for the main neurotransmitters
including glutamate and γ-aminobutyric acid (GABA), and the receptors for Ca 2+ , some
taste and pheromone molecules, as well as some orphan receptors. Class-C GPCRs
possess a heptahelical domain (HD) involved in heterotrimeric G-protein activation, but
most of them also have a large extracellular Venus Fly Trap (VFT) domain responsible
for agonist recognition and binding. Class -C GPCRs are dimers, either homo or
hetero-dimers. GABAB receptor is consisted of GABAB1 and GABAB2 subunits and
was the first heteromeric GPCR identified. The VFT domain of GABAB1 subunit
contains binding sites for neurotransmitter, agonists or antagonists, while the HD
domain of GABAB2 subunit is responsible for G-protein coupling. Therefore, both
subunits are necessary for a functional GABAB receptor. In this study, we demonstrated
the specific role of each subunit in ligand recognition, intramolecular transduction,
G-protein activation, and allosteric modulation. We also showed that the specific
activation of GABAB receptor leads to G-protein activation, which in turn activate
downstream signaling such as MAPK and PI3K/Akt pathway through trans-activation
of a receptor tyrosine kinase (RTK). To the best of our knowledge, this is the time to
report the trans-activation of a RTK by GABAB receptor.