Pharmacological Reviews Get Tables of Contents delivered automatically
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     


0031-6997/07/5903-225-250$7.00
Pharmacol Rev 59:225-250, 2007

This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Conn, P. M.
Right arrow Articles by Janovick, J. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Conn, P. M.
Right arrow Articles by Janovick, J. A.

G Protein-Coupled Receptor Trafficking in Health and Disease: Lessons Learned to Prepare for Therapeutic Mutant Rescue in Vivo

P. Michael Conn, Alfredo Ulloa-Aguirre, Joel Ito and Jo Ann Janovick

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.)

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
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.

Address correspondence to: Michael Conn, ONPRC/OHSU, 505 NW 185th Ave., Beaverton, Oregon 97006. E-mail: connm{at}ohsu.edu




This article has been cited by other articles:


Home page
 J. Biol. Chem.Home page
J. L. Wacker, D. B. Feller, X.-B. Tang, M. C. DeFino, Y. Namkung, J. S. Lyssand, A. J. Mhyre, X. Tan, J. B. Jensen, and C. Hague
Disease-causing Mutation in GPR54 Reveals the Importance of the Second Intracellular Loop for Class A G-protein-coupled Receptor Function
J. Biol. Chem., November 7, 2008; 283(45): 31068 - 31078.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Pharmacol.Home page
P.-A. Vidi, B. R. Chemel, C.-D. Hu, and V. J. Watts
Ligand-Dependent Oligomerization of Dopamine D2 and Adenosine A2A Receptors in Living Neuronal Cells
Mol. Pharmacol., September 1, 2008; 74(3): 544 - 551.
[Abstract] [Full Text] [PDF]

Home page
 Pharmacol. Rev.Home page
D. J. Muller, N. Wu, and K. Palczewski
Vertebrate Membrane Proteins: Structure, Function, and Insights from Biophysical Approaches
Pharmacol. Rev., March 1, 2008; 60(1): 43 - 78.
[Abstract] [Full Text] [PDF]


HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
All ASPET Journals Molecular Pharmacology Pharmacological Reviews
Molecular Interventions Drug Metabolism and Disposition
Copyright © 2007 by the American Society for Pharmacology and Experimental Therapeutics