Pharmacological Chaperones Correct Misfolded GPCRs and Rescue Function: Protein Trafficking as a Therapeutic Target - GPCR Signalling Complexes: Synthesis, Assembly, Trafficking and Specificity - page 255

Abstract G-protein-coupled receptors (GPCRs) are a large superfamily of plasma
membrane proteins that play central roles in transducing endocrine, neural and
sensory signals. In humans, more than 30 disorders are associated with mutations
in GPCRs and these proteins are common drug development targets, with 30-50%
of drugs targeting them. GPCR mutants are frequently misfolded, recognized as
defective by the cellular quality control system, retained in the endoplasmic reticu-
lum and do not traffic to the plasma membrane. The use of small molecules chap-
erones (pharmacological chaperones or “pharmacoperones”) to rescue misfolded
GPCRs has provided a new approach for treatment of human diseases caused by
misfolding and misrouting. This chapter provides an overview of the molecular
basis of this approach using the human gonadotropin-releasing hormone receptor
(hGnRHR) as model for treatment of conformational diseases provoked by
misfolded GPCRs.

Keywords Gonadotropin-releasing hormone receptor ￿ G protein coupled receptor
￿ Misfolding ￿ Pharmacological chaperone ￿ Pharmacoperone

Abbreviations

ER Endoplasmic reticulum

GnRH Gonadotropin-releasing hormone

GPCR G-protein coupled receptors

hGnRHR Human gonadotropin-releasing hormone receptor

HH Hypogonadotropic hypogonadism

HTS High throughput screening

PM Plasma membrane

QCS Quality control system

tTA Tetracycline-controlled transactivator

WT Wild-type

14.1 Introduction

G-protein coupled receptors (GPCRs) constitute a large superfamily of cell surface
plasma membrane proteins that transduce signals from outside to inside of the cell
by coupling to heterotrimeric G-proteins (Dong et al. 2007 ; Ulloa-Aguirre and