Function of GB1 and GB2 subunits in G protein coupling of GABA(B) receptors

Many G protein-coupled receptors (GPCRs) have recently been shown to dimeri ze, and it was suggested that dimerization may be a prerequisite for G prot ein coupling. gamma -aminobutyric acid type B (GABAB) receptors (GPCRs for GABA, a major inhibitory neurotransmitter in the brain) are obligate hetero dimers of homologous GB1 and GB2 subunits, neither of which is functional o n its own. This feature of GABA(B) receptors allowed us to examine which of the eight intracellular segments of the heterodimeric receptor were import ant for G protein activation. Replacing any of the three intracellular loop s of GB2 with their GB1 counterparts resulted in nonfunctional receptors. T he deletion of the complete GB2 C terminus significantly attenuated the rec eptor function; however, the proximal 36 residues were sufficient for recon stitution of wild type-like receptor activity. In contrast, the GB1 C termi nus could be deleted and GB1 intracellular loops replaced with their GB2 or mGluR1 equivalents without affecting the receptor function. In addition, a large portion of the GB1 i2 loop could be replaced with a random coil pept ide without any functional consequences. Thus, GB2 intracellular segments a re solely responsible for specific coupling of GABA(B) receptors to their p hysiologic effectors, G(i) and G protein-activated K+ channels. These findi ngs strongly support a model in which a single GPCR monomer is sufficient f or all of the specific G protein contacts.