Allosteric interactions between GB1 and GB2 subunits are required for optimal GABA(B) receptor function

Recent studies on G-protein-coupled receptors revealed that they can dimeri ze. However, the role of each subunit in the activation process remains unc lear. The gamma -amino-n-butyric acid type B (GABA(B)) receptor is comprise d of two subunits: GB1 and GB2. Both consist of an extracellular domain (EC D) and a heptahelical domain composed of seven transmembrane alpha -helices , loops and the C-terminus (HD). Whereas GB1 ECD plays a critical role in l igand binding, GB2 is required not only to target GB1 subunit to the cell s urface but also for receptor activation. Here, by analysing chimeric GB sub units, we show that only GB2 HD contains the determinants required for G-pr otein signalling. However, the HD of GB1 improves coupling efficacy. Conver sely, although GB1 ECD is sufficient to bind GABA(B) ligands, the ECD of GB 2 increases the agonist affinity on GB1, and is necessary for agonist activ ation of the receptor. These data indicate that multiple allosteric interac tions between the two subunits are required for wild-type functioning of th e GABA(B) receptor and highlight further the importance of the dimerization process in GPCR activation.