Receptor biology

Delineating the Roles of GB1 and GB2

Science's STKE  11 Dec 2001:
Vol. 2001, Issue 112, pp. tw455
DOI: 10.1126/stke.2001.112.tw455

Functional γ-aminobutyric acid (GABA) receptors are composed of heterodimers of two similar subunits GB1 and GB2. The NH2-termini of both subunits have a domain that is highly similar to the one found in bacterial periplasmic amino acid-binding proteins (PBPs); however, only the PBP-like domain in GB1 is essential for binding GABA. Two papers this week further elucidate the functions of GB1 and GB2 in the GABAB receptor. Two models have been posited to explain the transmission of receptor occupancy to the activation of G proteins associated with the GABA receptor. The peptide-linker model suggests that signaling depends on a shift in the peptide linker segment between the PBP and the heptahelical structures of each receptor subunit. The direct contact model predicts that the PBP-like domains contact the heptahelical domains and that these contact points shift upon ligand binding. Margeta-Mitrovic et al. showed that perturbations in the peptide-linker region did not affect GABAB receptor function, suggesting that the peptide linker model might not account for GABAB receptor activation. Additionally, combinations of GABAB receptors composed of wild-type GB1 and a GB2 chimera containing the GB1 PBP-like domain had ligand-independent basal activity, whereas receptors composed of wild-type GB2 and a GB1 mutant containing the GB2 PBP-like domain did not respond to GABA. Receptors containing GB1 and GB2 whose PBP-like domains were swapped responded to GABA in a manner similar to wild-type subunit-composed receptors. Thus, heterodimerization of subunits composed of different PBP-like domains seems to be important for the normal function of GABA receptors. In an accompanying paper, the same group evaluated the roles of the COOH-termini of GB1 and GB2 in the activation of the GABAB receptor. The deletion of the GB1 COOH-terminus did not affect receptor activity, nor did the replacement of GB1 intracellular loops with the same region from GB2, indicating that at least the COOH-terminal region of GB1 might not be required for the activation of G protein-activated K+ channels (GIRKs). Removal of the GB2 COOH-terminus or replacement with the same region from GB1 resulted in nonfunctional GABAB receptors. Thus, the GB1 subunit may be responsible for binding GABA (through the PBP-like domain), whereas GB2 might be responsible for signaling to GIRKs through the activation of G proteins. These findings may underscore the essential nature of subunit heterodimerization for proper GABAB receptor functioning.

M. Margeta-Mitrovic, Y. N. Jan, L. Y. Jan, Ligand-induced signal transduction within heterodimeric GABAB receptor. Proc. Natl. Acad. Sci. U.S.A. 98, 14643-14648 (2001). [Abstract] [Full Text]

M. Margeta-Mitrovic, Y. N. Jan, L. Y. Jan, Function of GB1 and GB2 subunits in G protein coupling of GABAB receptors. Proc. Natl. Acad. Sci. U.S.A. 98, 14649-14654 (2001). [Abstract] [Full Text]