G protein-coupled receptor trafficking in health and disease: lessons learned to prepare for therapeutic mutant rescue in vivo.
G protein-coupled receptors (GPCR) comprise the largest family of drug targets. This is not surprising as many signaling systems rely on this class of receptor to convert external and internal stimuli to intracellular responses. As is the case with other membrane proteins, GPCRs are subjected to a stringent quality control mechanism at the endoplasmic reticulum, which ensures that only correctly folded proteins enter the secretory pathway. Because of this quality control system, point mutations resulting in protein sequence variations may result in the production of misfolded and disease-causing proteins that are unable to reach their functional destinations in the cell. There is now a wealth of information demonstrating the functional rescue of misfolded mutant receptors by small nonpeptide molecules originally designed to serve as receptor antagonists; these small molecules ("pharmacoperones") serve as molecular templates, promoting correct folding and allowing the mutants to pass the scrutiny of the cellular quality control system and be expressed at the cell surface membrane. Two of these systems are especially well characterized: the gonadotropin-releasing hormone and the vasopressin type 2 receptors, which play important roles in regulating reproduction and water homeostasis, respectively. Mutations in these receptors can lead to well defined diseases that are recognized as being caused by receptor misfolding that may potentially be amenable to treatment with pharmacoperones. This review is focused on protein misfolding and misrouting related to various disease states, with special emphasis on these two receptors, which have proved to be of value for development of drugs potentially useful in regulating GPCR trafficking in healthy and disease states.
Conn
P Michael
PM
Divisions of Neuroscience and Reproductive Biology, ONPRC/OHSU, Beaverton, OR 97006, USA. connm@ohsu.edu
Ulloa-Aguirre
Alfredo
A
Ito
Joel
J
Janovick
Jo Ann
JA
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D015195:Drug Design; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism*; D008024:Ligands; D018832:Molecular Chaperones / Q000378:metabolism; D008969:Molecular Sequence Data; D009154:Mutation; D010600:Pharmacology; D017510:Protein Folding; D021381:Protein Transport; D011966:Receptors, LHRH / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017483:Receptors, Vasopressin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
D008024:Ligands; D018832:Molecular Chaperones; D011966:Receptors, LHRH; D017483:Receptors, Vasopressin