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The gamma-aminobutyric acid type B (GABAB) receptor is an allosteric complexmade of two subunits, GABAB1 (GB1) and GABAB2 (GB2). Both subunits are composedof an extracellular Venus flytrap domain (VFT) and a heptahelical domain (HD).GB1 binds GABA, and GB2 plays a major role in G-protein activation as well asin the high agonist affinity state of GB1. How agonist affinity in GB1 isregulated in the receptor remains unknown. Here, we demonstrate that GB2 VFT isa major molecular determinant involved in this control. We show that isolatedversions of GB1 and GB2 VFTs in the absence of the HD and C-terminal tail canform hetero-oligomers as shown by time-resolved fluorescence resonance energytransfer (based on HTRF technology). GB2 VFT and its association with GB1 VFTcontrolled agonist affinity in GB1 in two ways. First, GB2 VFT exerted a directaction on GB1 VFT, as it slightly increased agonist affinity in isolated GB1VFT. Second and most importantly, GB2 VFT prevented inhibitory interactionbetween the two main domains (VFT and HD) of GB1. According to this model, wepropose that GB1 HD prevents the possible natural closure of GB1 VFT. Incontrast, GB2 VFT facilitates this closure. Finally, such inhibitory contactsbetween HD and VFT in GB1 could be similar to those important to maintain theinactive state of the receptor.

Molecular determinants involved in the allosteric control of agonist affinity in the GABAB receptor by the GABAB2 subunit