Time-Resolved Förster Resonance Energy Transfer-Based Technologies to Investigate G Protein-Coupled Receptor Machinery: High-Throughput Screening Assays and Future Development - Progress in Molecular Biology and Translational Science - page 296

4.2. Drugs targeting a protein complex
4.2.1 Oligomers as new therapeutic targets
Over the past two decades, the simple model for GPCR activation—one
GPCR protomer activating one single G protein heterotrimer—has been
challenged by an increasing amount of data showing that GPCR oligomer-
ization, either homo- or heteromerization, is a common phenomenon. 10
Oligomerization has been shown to influence many different properties
of GPCRs as illustrated below, and thus receptor dimers or oligomers,
and especially heteromers, often possess unique characteristics totally
different from those of their individual composing protomers and/or they
promote regulation phenomena of one subunit by the other (e.g., allosteric
modulation between units), making them unique and innovative targets to
analyze. Thus, these oligomers represent innovative and challenging targets
for drug discovery, and assays to identify them and to study their properties
will certainly be developed in the near future.
4.2.1.1 Effect of oligomerization on GPCR cell-surface expression
First, oligomerization has been shown to influence GPCR early biosynthesis
in the endoplasmic reticulum and their maturation. For example, the GABA B
receptor, a member of the class-C GPCR, was one of the first obligatory
heteromers described in the literature. 52 It is composed of two subunits,
GABA B1 and GABA B2 , the first one being responsible for GABA binding
and the second for G protein coupling. 53,54 GABA B2 synthesis is necessary
for the functional heterodimer to reach the cell surface. Indeed, the
interaction between the two subunits is necessary to mask the retention
motif contained in GABA B1 C-terminus. 55,56 Other examples of obligatory
dimers are found in the class-C GPCR, where the sweet and umami tastes
are generated by functional responses from obligate heterodimeric pairs of
T1 taste receptors, 57 and where the mGluRs, responsible for modulating
fast glutamatergic transmission in the brain, are strict and obligatory
homodimers linked by a disulfide bond. 26,58 GPCR oligomerization also
influences other regulatory processes such as internalization, trafficking, and
recycling. The CXCR4 and CCR5 receptors, for example, two members
of the class-A GPCR and coreceptors for HIV entry in human cells, were
shown to heteromerize, modulating T-cell function and generating specific
internalization and degradation properties for the complex as compared to
those of each protomer. 59