Trafficking and quality control of the gonadotropin releasing hormone receptor in health and disease

In order to serve as enzymes, receptors and ion channels, proteins require structural precision. This is monitored by a cellular quality control system (QCS) that rejects misfolded proteins and thereby protects the cell against aberrant activity. Misfolding can result in protein molecules that retain intrinsic function, yet become misrouted within the cell; these cease to perform normally and result in disease. A therapeutic opportunity exists to correct misrouting and rescue mutants using “pharmacoperones” (small molecular folding templates, often peptidomimetics, which promote correct folding and rescue) thereby restoring function and potentially curing the underlying disease. Because of its small size, the GnRH (gonadotropin-releasing hormone) receptor (GnRHR) is an excellent model for GPCR (G protein-coupled receptor) and has allowed elucidation of the precise biochemical mechanism of pharmacoperone action necessary for rational design of new therapeutic agents. This review summarizes what has been learned about the structural requirements of the GnRHR that govern its interaction with the QCS and now presents the potential for the rational design of pharmacoperones. Because of the role of protein processing, this approach is likely to be applicable to other GCPCs and other proteins in general.