Pharmacological Chaperones Correct Misfolded GPCRs and Rescue Function: Protein Trafficking as a Therapeutic Target - GPCR Signalling Complexes: Synthesis, Assembly, Trafficking and Specificity - page 264

provoke trapping of the endothelin-B receptor have been detected in some patients
with Hirschsprung's disease or aganglionic megacolon (Fuchs et al. 2001 ; Tanaka
et al. 1998 ). Finally, intracellular retention of the chemokine receptor 5 at the ER
has also been observed in a subset of subjects with resistance to HIV infection
(Rana et al. 1997 ) .
The use of different chemical classes of pharmacoperone molecules to rescue
misfolded GPCRs leading to disease has been reported. These include: pharmaco-
perones for misfolded hGnRHRs, V2Rs, rhodopsin, LH and FSHRs, MC1R, MC3R
and MC4R, and the calcium sensing receptor (Table 14.1 ). Different chemical
classes of peptidomimetics (indoles, quinolones, erythromycin-derived macrolides
and others), originally developed as GnRH peptidomimetic antagonists, have
consistently shown pharmacoperone properties for rescuing a number of naturally
occurring misfolded hGnRHRs; the efficacy of the tested compounds was propor-
tional to the binding affinity of the drug for the WT receptor, and in general, drugs
that rescue one mutant, also rescue others, even when the mutations are far apart
(Janovick et al. 2003a ) .
In the case of the V2R, it has been shown that distinct cell membrane permeable
antagonists effectively rescue in vitro function of several misfolded, traffic-defective
mutants that cause diabetes insipidus in humans (Albright et al. 1998 ; Bernier et al.
2004c, 2006 ; Morello et al. 2000b ; Serradeil-Le Gal et al. 1996 ) . These fi ndings are
important since the majority (~70%) of V2R mutations, leading to disease, are due
to receptor misrouting (Bichet 2006 ). Further, the peptidomimetic V1 A R/V2R
antagonist SR49059 (Serradeil-Le Gal et al. 1996 ) proved to be effective in rescuing
function of the R 137 H, W 164 S, and des 185-193 V2R mutants in patients with nephro-
genic diabetes insipidus; administration of this pharmacoperone provoked a drop in
urine production and water intake as well as a significant increase in urine osmolar-
ity (Bernier et al. 2006 ). In rhodopsin retinitis pigmentosa, the majority of rhodop-
sin mutations (~89%) provoke misfolding of the receptor protein leading to its
intracellular retention and aggregation and eventually cell death. Functional rescue
of the T 17 M and P 23 H misfolded mutants causing retinitis pigmentosa has been
achieved by exposing HEK-293 cells to 11- cis -retinal or 11- cis- 7-ring-retinal (a
seven-membered ring variant of 11- cis -retinal), the chromophore of rhodopsin
involved in the photoactivation process (Krebs et al. 2010 ; Noorwez et al. 2004,
2008 ). Further, administration of vitamin A palmitate to transgenic mice with the
opsin T 17 M mutation provoked a significant decrease in retinal degeneration (Li
et al. 1998 ). In the vast majority of melanocortin-4 receptor mutants, which have
been associated with monogenic obesity, the mutant receptors are retained intracel-
lularly due to misfolding (Fan and Tao 2009 ; Tao 2010 ). In these misfolded mutant
MC4Rs, both the pharmacoperone ML00253764 and the chemical chaperone
4-phenylbutyric acid rescued PM expression and function of the mutant receptors to
different extents (Fan et al. 2009 ; Fan and Tao 2009 ; Granell et al. 2010 ; Vos et al.
2004 ). In the case of PM expression-deficient m-opioid receptors and melanin con-
centrating hormone receptor-1 mutants, different cell permeable agonists and
antagonists have been also shown to effectively enhance cell surface expression of
the mutant receptors (Chaipatikul et al. 2003 ; Fan et al. 2005b ) .