Modulation of cell surface GABAB receptors by desensitization, trafficking and regulated degradation

Figure 1 Structural organization of GABA_B receptors. Functional GABA_B receptors are heterodimers composed of the two subunits GABA_B1 and GABA_B2. Both subunits are heptahelical membrane proteins with a large extracellular located N-terminal domain containing a “Venus flytrap” module and a large intracellular C-terminal domain containing a coiled-coil protein-protein interaction module. GABA_B1 and GABA_B2 heterodimerize via their “Venus flytrap” and coiled-coiled domains. An endoplasmic reticulum (ER) retention/retrieval signal is present distal to the coiled-coil domain in GABA_B1 and prevents ER exit of GABA_B1 unless it is masked by heterodimerization with GABA_B2. The “Venus flytrap” module of GABA_B1 constitutes the GABA binding site, whereas that of GABA_B2 is inactive and not involved in ligand binding. Instead, the heptahelical domain of GABA_B2 contains a binding site for allosteric modulators, which affects the affinity of ligands binding to the GABA site. Binding of GABA results in the recruitment and activation of Gαi/o proteins via GABA_B2. The activated Gαi/o subunit inhibits the adenylyl cyclase, resulting in lowered cAMP levels, while the Gβγ dimer activates K⁺ channels and inhibits Ca²⁺ channels, leading in either case to neuronal inhibition. There exist two isoforms of GABA_B1, named GABA_B1a and GABA_B1b, which are generated by alternative promoter usage. They only differ by the additional presence of two so-called “sushi repeats” (protein-protein interaction modules) in the N-terminal domain of GABA_B1a. GABA: γ-Aminobutyric acid; ATP: Adenosine-5'-triphosphate; cAMP: 3'-5'-cyclic adenosine monophosphate.