Regulated GPCR Trafficking to the Plasma Membrane: General Issues and the CCR5 Chemokine Receptor Example - GPCR Signalling Complexes: Synthesis, Assembly, Trafficking and Specificity - page 97

6.3 Accessory Proteins Promoting GPCR Forward Export

or Involved in Their Cytoplasmic Retention

During the years following the key observations at the basis of the new paradigm
of regulated GPCR export, studies addressed different mechanistic issues of the
question: the role of GPCR-interacting proteins in receptor retention or export, the
molecular mechanisms of release from intracellular tethers, the “STOP” and “GO”
signals carried by GPCRs, which are perceived by the export machinery, and the
routes (cellular motors, coat proteins, small GTPases) to transport receptors to the
cell surface. The last two aspects, which are treated in other chapters of this topic
and have been the object of recent reviews (Dong et al. 2007 ) ; Wang and Wu 2012 ) ,
will not be detailed here.
As mentioned above, odr-4 and RAMPs function as escort proteins that bind
nascent GPCRs in the ER and accompany them to the Golgi complex and to the
plasma membrane, where they remain associated with the receptor. After these
pioneering studies, several other GPCR escorts have been described (Table 6.1 ).
Interestingly, dysfunction of several GPCR escort proteins has been associated with
disease. Mutations of the MRAP gene are involved the familial glucocorticoid
deficiency, characterized by the resistance of the adrenal cortex to adrenocorticotropin
(Metherell et al. 2005 ). Mutations of Receptor Expression Enhancing Protein 1
(REEP1), an escort for odorant receptors, have recently been correlated with auto-
somal dominant hereditary spastic paraplegia (HSP) type SPG31 (Zuchner et al.
2006 ; Beetz et al. 2008 ), although the underlying pathophysiological mechanisms
remain to be elucidated. Abnormal serotonin signaling has been implicated in the
pathophysiology of depression. A depression-like phenotype has been reported in
knockout mice for p11 (Svenningsson et al. 2006 ) a member of the S100 EF-hand
calcium-dependent signaling modulators (Donato 1999 ) , which speci fi cally interacts
with serotonin 5-HT 1B receptors (5-HT 1B R). Cell surface density and function of
5-HT 1B Rs are decreased in these mice, indicating that p11 is an escort for 5-HT 1B R .
Interestingly, p11 was increased in the brain of mice treated with antidepressants
and was also found reduced in depressed patients. Moreover, adeno virus-mediated
transfer of the gene encoding p11 to the nucleus accumbens rescued the depression-
related behavioral disorders of mice in which endogenous p11 had been genetically
knocked out (Alexander et al. 2010 ) .
Tissue distribution of nearly all these escort proteins is broader than that of their
cognate GPCR(s) suggesting that they might facilitate the surface expression of
additional GPCRs, as shown in the case of RTP (Receptor Transporting Proteins)
and REEP proteins. These proteins were at first described as escorts for odorant
receptors (Saito et al. 2004 ) but subsequently RTP and REEP mRNAs were detected
in human circumvallate papillae and testis, the sites of bitter taste receptor (TAS2R)
expression. Experiments in heterologous cells confirmed the enhancement of
TAS2R cell surface targeting upon interaction with RTP3-4 and REEPs (Behrens
et al. 2006 ). Alternatively, for some escort proteins, targeting GPCRs to the cell
surface might be viewed as a “moonlighting job” as in the case for the CD4 protein