The C-terminal domains of the GABA(B) receptor subunits mediate intracellular trafficking but are not required for receptor signaling

GABA(B) receptors are G-protein-coupled receptors that mediate slow synapti c inhibition in the brain and spinal cord. These receptors are heterodimers assembled from GABA(B1) and GABA(B2) subunits, neither of which is capable of producing functional GABA(B) receptors on homomeric expression. GABA(B1 ), although able to bind GABA, is retained within the endoplasmic reticulum (ER) when expressed alone. In contrast, GABA(B2) is able to access the cel l surface when expressed alone but does not couple efficiently to the appro priate effector systems or produce any detectable GABA-binding sites. In th e present study, we have constructed chimeric and truncated GABA(B1) and GA BA(B2) subunits to explore further GABA(B) receptor signaling and assembly. Removal of the entire C-terminal intracellular domain of GABA(B1) results in plasma membrane expression without the production of a functional GABA(B ) receptor. However, coexpression of this truncated GABA(B1) subunit with e ither GABA(B2) or a truncated GABA(B2) subunit in which the C terminal has also been removed is capable of functional signaling via G-proteins. In con trast, transferring the entire C-terminal tail of GABA(B1) to GABA(B2) lead s to the ER retention of the GABA(B2) subunit when expressed alone. These r esults indicate that the C terminal of GABA(B1) mediates the ER retention o f this protein and that neither of the C-terminal tails of GABA(B1) or GABA (B2) is an absolute requirement for functional coupling of heteromeric rece ptors. Furthermore although GABA(B1) is capable of producing GABA-binding s ites, GABA(B2) is of central importance in the functional coupling of heter omeric GABA(B) receptors to G-proteins and the subsequent activation of eff ector systems.