Escorts take the lead molecular chaperones as therapeutic targets

Abstract

The functional and physiological diversity of transmembrane receptors results from factors that influence the pharmacology, signaling, and trafficking of these receptors. Receptor mutations and other modifications may lead to misfolding, intracellular retention, and ineffective signaling of transmembrane receptors. The importance of such mutations is highlighted by the fact that various diseases have been linked to mutations that lead to ineffective signaling of these receptors, resulting from the retention of receptors in intracellular compartments. Studies focused on understanding the regulation of trafficking and cell surface expression of newly synthesized receptors have highlighted molecular chaperones as key regulators of receptor maturation and sorting. In this chapter, we discuss the functions of molecular chaperones in the regulation of seven-transmembrane-containing G-protein-coupled receptor function and trafficking and explore ways in which chaperones can serve as novel therapeutic targets.

Fig. 1

Proposed model for the action of pharmacological chaperones. Left panel: Mutated receptors and wild-type receptors that are misfolded are retained in the ER by the cellular quality-control system and targeted for proteasomal degradation. Subsequently, these receptors are not able to bind ligand and participate in signaling. Right panel: Treatment of cells with cell permeable pharmacological chaperones leads to stabilization of the receptor structure and restoration of the cell surface expression of the receptors. The receptors are therefore able to bind ligands and function in signaling processes.