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The G‐protein‐coupled receptor (GPCR) activated by the neurotransmitter GABA is made up of two subunits, GABA B1  and GABA B2 . GABA B1  binds agonists, whereas GABA B2  is required for trafficking GABA B1  to the cell surface, increasing agonist affinity to GABA B1 , and activating associated G proteins. These subunits each comprise two domains, a Venus flytrap domain (VFT) and a heptahelical transmembrane domain (7TM). How agonist binding to the GABA B1  VFT leads to GABA B2  7TM activation remains unknown. Here, we used a glycan wedge scanning approach to investigate how the GABA B  VFT dimer controls receptor activity. We first identified the dimerization interface using a bioinformatics approach and then showed that introducing an N‐glycan at this interface prevents the association of the two subunits and abolishes all activities of GABA B2 , including agonist activation of the G protein. We also identified a second region in the VFT where insertion of an N‐glycan does not prevent dimerization, but blocks agonist activation of the receptor. These data provide new insight into the function of this prototypical GPCR and demonstrate that a change in the dimerization interface is required for receptor activation.

Functioning of the dimeric GABA B receptor extracellular domain revealed by glycan wedge scanning