Role of Chaperones in G Protein Coupled Receptor Signaling Complex Assembly - GPCR Signalling Complexes: Synthesis, Assembly, Trafficking and Specificity - page 24

a b c Cell Surface

Cell Surface

Cell Surface

No Signaling

Golgi

Golgi

Golgi

No Export

ER Lumen

ER Lumen ER Lumen

µ- opioid

GbR1 δ- opioid

GbR2

CRLR Immature CRLR

Chaperone

RTP4 Trimeric G Protein Complex

Trimeric G Protein Complex

Trimeric G Protein Complex

RAMP1

Fig. 2.1 Molecular Chaperones Play a Crucial Role in the Export of GPCRs from the ER to
the Plasma Membrane . ( a ) The dimerization of GABA B receptor subunits: when expressed as
monomers, GbR1 is retained in the ER membrane while GbR2 is transported to the plasma
membrane but remains non-functional. Molecular chaperones facilitate the dimerization of the two
receptors by masking the ER-retention motif in GbR1, resulting in the expression of a fully func-
tional receptor dimer at the cell surface. ( b ) RTP4 modulates the targeting of m , d -opioid heterodimer
to the cell surface. The association of the Golgi chaperone, RTP4, with the opioid receptors increases
the level of expression of the heterodimer. ( c ) RAMP1 facilitates the maturation of CRLR. The
interaction of RAMP1 with the immature form of CRLR aids in the complete folding of the receptor
and transferring it to the cell surface. ABB: ER endoplasmic reticulum, GbR1 GABA B receptor 1,
GbR2 GABA B receptor 2, m opioid mu opioid, d opioid delta opioid, RTP4 receptor transport
protein4, CRLR calcitonin-receptor-like receptor, RAMP1 receptor activity-modifying protein1

Several reports have now demonstrated the pertinence of oligomerization for
some receptors in vivo . While GPCR biosynthesis and transport towards the cell
surface remains poorly characterized, their exit from the endoplasmic reticulum
(ER) has been defined as a crucial step in controlling their expression (Petaja-
Repo et al. 2000). Incompletely folded or misfolded proteins are retained in the
ER and are eventually targeted for degradation, while only correctly folded pro-
teins are able to transit out of the ER (Reddy and Corley 1998 ) . The now standard
example of this ER quality control cycle in the GPCR family is the metabotropic
g- aminobutyric acid (GABA) receptor. This functional receptor is formed by two
subunits, GbR1 and GbR2. When expressed alone, GbR1 has a carboxy-terminal
ER retention motif that retains the receptor in the ER, whereas GbR2 is expressed
at the cell surface but is not capable of activating effector pathways (Margeta-
Mitrovic et al. 2000 ; Ng et al. 1999 ; Robbins et al. 2001 ; Sullivan et al. 2000 ) .
Co-expression and heterodimerization of the two subunits masks the ER retention
motif on GbR1 and allows a functional, dimeric signalling complex to be expressed
at the cell surface (Fig. 2.1 ). Although a general role for heterodimerization and/