Gatekeepers Controlling GPCR Export and Function

Regulated export of G protein-coupled receptors (GPCRs) from intracellular stores involves chaperones and escort proteins, which promote their progression to the cell surface, and gatekeepers, which retain them in intracellular compartments. Functional γ-aminobutyric acid (GABA)B receptors, the paradigm of this phenomenon, comprise GB1 and GB2 subunits forming a heterodimer. GB1 is retained in the endoplasmic reticulum (ER) in the absence of GB2. A specific ER-resident gatekeeper, prenylated Rab acceptor family 2 (PRAF2), is involved in GB1 retention and prevents its progression into the biosynthetic pathway. GB1 can be released from PRAF2 only on competitive interaction with GB2. PRAF2 is ubiquitous and belongs to a subgroup of the mammalian Ypt-interacting protein (Yip) family. Several other GPCRs are likely to be regulated by Yip proteins, which might be involved in the pathophysiology of human diseases that are associated with impaired receptor targeting to the cell surface.

TrendsFunctional GABAB receptors are obligate heterodimers of the GB1 and GB2 subunits.The agonist binding GB1 is retained inside the cells in the absence of association with GB2.GB2 competitively releases GB1 from PRAF2, a specific ER-resident gatekeeper.The stoichiometry of PRAF2 relative to GB1 and GB2 is a key parameter of GABAB function in vivo.