GPCR Oligomerization: Contribution to Receptor Biogenesis - GPCR Signalling Complexes: Synthesis, Assembly, Trafficking and Specificity - page 57

receptor. Co-expression of this ER-retained form with either wild type CXCR1 or
CXCR2, prevented the delivery of these receptors to the cell surface, demonstrating
CXCR1/CXCR2 homo- and heterodimerization in the ER (Wilson et al. 2005 ) .
Co-immunoprecipitation studies of vasopressin and oxytocin receptors indicated
that the immature receptors, which are located in the ER, form both homo- and
heterodimers (Terrillon et al. 2003 ). These examples show that heterodimerization
between two closely related members of family A GPCRs can be necessary for
proper cell-surface expression of the receptor. In addition, dimerization seems to
also occur between less closely related GPCR members. A study of olfactory recep-
tors in a heterologous system showed that the mouse 71 (M71) olfactory receptor
exhibited very poor surface expression, and that this cell surface localization was
dramatically improved by co-expression of the b 2 -adrenergic receptor (Hague et al.
2004 ). This suggests that the M71 olfactory receptor forms dimers with the b 2 -
adrenergic receptor in the ER and that this interaction is required for transport of
M71 olfactory receptors to the membrane.

3.6.2 Family B

Little is known about the existence of oligomeric complexes for family B receptors.
BRET analysis has demonstrated that the prototypic family B secretin receptor
forms ligand-independent oligomeric complexes in the PM (Ding et al. 2002 ) . Next,
human vasoactive intestinal polypeptide receptors (VPAC1 and VPAC2 receptors),
which represent the closest structurally related receptor to the secretin receptor, also
form constitutive oligomers with both themselves and the secretin receptor.
Morphological FRET localization studies of pairs of CFP- and YFP-tagged recep-
tors co-expressed in COS cells show the presence of homo-oligomers, both in the
PM and in the biosynthetic compartments such as the ER and Golgi (Harikumar
et al. 2006 ). Interestingly, the formation of heteromers between the VPAC1 or
VPAC2 receptor with the secretin receptor was visualized in the intracellular com-
partments but not on the cell surface (Harikumar et al. 2006 ) .

3.6.3 Family C

The clearest example of obligatory oligomerization is represented by the GABA B1
and GABA B2 receptors, the two subunits of the GABA B receptor (Margeta-Mitrovic
et al. 2000 ) . The GABA B1 receptor subunit that contains the structural elements for
ligand binding, but not for G protein-coupling, is retained in the ER unless it is co-
expressed with the GABA B2 receptor subunit. The GABA B2 receptor subunit does
not possess the ability to bind ligands, but instead mediates G protein-coupling and
is able to reach the cell surface alone. Dimerization involves interactions between
the C-terminal coiled-coil domains of the GABA B receptor subunits, which masks
an ER retention motif located in the C-terminal tail of the GABA B1 receptor subunit