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Divisions of Neuroscience and Reproductive Biology (P.M.C., A.U.-A., J.A.J.), Oregon National Primate Research Center (P.M.C., A.U.-A., J.I., J.A.J.), and Departments of Physiology and Pharmacology and Cell and Developmental Biology (P.M.C.), Oregon Health and Science University, Beaverton, Oregon; and Research Unit in Reproductive Medicine, Hospital de Ginecobstetricia "Luis Castelazo Ayala," Instituto Mexicano del Seguro Social, Mexico City, Mexico (P.M.C., A.U.-A.)
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 stringentquality 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.
Abstract I. Introduction II. Endoplasmic Reticulum Quality Control System and Molecular Chaperones III. Physiology of the Gonadotropin-Releasing Hormone Receptor and Vasopressin Type 2 Receptor Systems A. The Human Gonadotropin-Releasing Hormone Receptor and Vasopressin Type 2 Receptor in Health and Disease B. Lessons from Comparison of the Gonadotropin-Releasing Hormone Receptor and Vasopressin Type 2 Receptor Systems: Selecting Likely Targets for Rescue by Pharmacoperones C. Relation between the Overall Receptor Structure and the Structure of the Ligand Binding Site D. Distribution of Mutations IV. Ligand and Receptor Frequency Modulation in Signaling Systems: Implications for Model Selection and the Timing of Pharmacoperone Administration in Vivo A. Frequency Modulation among Primate Gonadotropin-Releasing Hormone Receptors B. Amino Acids Associated with Control of Plasma Membrane Expression C. Amino Acid Positions Associated with Control of Ligand Binding Affinity D. Ligand Binding Affinity as a Squelch Control E. Receptor Concentration at the Plasma Membrane as a Gain Control V. Do Pharmacoperones Need to Be Present at the Time of Mutant Synthesis? VI. The Dominant-Negative Effect and Receptor Rescue VII. Will Pharmacoperone Drugs Be Species-Specific? Selecting the Correct Models for Drug Development VIII. Endogenous Chaperones as a Potential Site for Therapeutic Intervention IX. In Vitro and in Vivo Studies with Pharmacoperones: How Close Are We to the Transferring of Discoveries from the Laboratory Bench to the Bedside? X. Conclusions
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