Divorce of obligatory partners in pain: disruption of GABA(B) receptor heterodimers in neuralgia.

It is now well established that G protein-coupled receptors can exist not only as homodimers, but also as heterodimers or higher order oligomers. However, whether and how dimerization of the receptors is regulated is poorly understood. In this issue of The EMBO Journal, the team of Marc Landry provides evidence for an intriguing mechanism by which—under pathological conditions—GABAB receptor heterodimers at the cell surface are disrupted and thereby inactivated. An impressive set of experiments thus reveals a novel mechanism regulating the number of functional GABAB receptors in the plasma membrane and shows that the receptor heterodimer may not be as stable as we previously thought. It is evident that dimerization and oligomerization at least of class A and C G protein-coupled receptors (GPCRs) play important roles in permitting or enhancing their cell surface trafficking (Milligan, 2010). The assembly process is thought to serve as a quality control mechanism to ensure that only fully mature and functional receptors reach the plasma membrane. The prototype of an obligatory heterodimer among GPCRs is the GABAB receptor, which controls excitability of neurons by mediating slow inhibitory neurotransmission (Gassmann and Bettler, 2012). Functional GABAB receptors are built from two related proteins termed as GABAB1 and GABAB2. Although both subunits display a similar structural organization—with a large extracellular domain containing a Venus fly-trap structure, seven transmembrane domains and a large intracellular located C-terminal domain—they serve distinct, complementary functions. GABAB1 binds the orthosteric ligands whereas GABAB2 recruits the G protein and is required for cell surface trafficking of the receptor complex by masking an ER