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The Serpentine Path: Advances in 7-Transmembrance Receptor Therapeutics

The Serpentine Path
Reported by
Catherine Zandonella

Posted November 26, 2008


Seven-transmembrane receptors (7TMRs) constitute the largest family of cell-surface receptors, regulating physiological processes from contractions of the heart to sensations of euphoria in the brain. The receptors are attractive targets for pharmacological therapeutics, and roughly 50% of currently marketed drugs work through them. The September 23, 2008, meeting at the Academy on 7TMR research brought leading researchers in the field together to discuss some of the latest developments.

They discussed structural biology studies on binding at allosteric sites, ligand-biased signaling, and the role of heterodimers in 7TMR signaling. Other topics included signaling downstream of the receptor and natural and pharmacological chaperones.

Web Sites

GPCRDB: Information system for G protein-coupled receptors
An informal collaboration of GPCR databases, including mutation data, ligand binding data, sequence annotations, and cross-references to other databases.

IUPHAR Database of G-Protein Coupled Receptors
A database of GPCRs, their ligands, and their properties.

National Institutes of Health's Molecular Libraries Probe Production Centers Network (MLPPCN)
The Molecular Libraries Program (MLP) aims to produce high quality small molecule probes and biological-chemical data and tools to help investigators in their identification and analysis of protein function, signaling and metabolic pathways, and cellular function important human health and disease.

Science Signaling
Science Signaling is a journal devoted to the topic of cell signaling. Its Database of Cell Signaling provides information on the components of cellular signaling pathways and their relations to one another.

Wikipedia entry for G-Protein Coupled Receptors
This Wikipedia entry provides basic information about GPCRs.

American Society for Pharmacology and Experimental Therapeutics (ASPET)
A scientific society whose members conduct basic and clinical pharmacological research in academia, industry, and the government.


Devi L, ed. 2005. The G Protein-Coupled Receptors Handbook. Humana Press, Totowa, NJ.

Lundstrom KH, Chiu ML, eds. 2005. G Protein-Coupled Receptors in Drug Discovery. CRC Press, Boca Raton, FL.

Seifert R, Wieland T, eds. 2005. G Protein-Coupled Receptors as Drug Targets: Analysis of Activation and Constitutive Activity. Series: Methods and Principles in Medicinal Chemistry. Wiley, Weinheim, Germany.

Journal Articles

Craig Lindsley

Brady AE, Jones CK, Bridges TM, et al. 2008. Centrally active allosteric potentiators of the M4 muscarinic acetylcholine receptor reverse amphetamine-induced hyperlocomotor activity in rats. J. Pharmacol. Exp. Ther. [Epub ahead of print]

Bridges TM, Brady AE, Kennedy JP, et al. 2008. Synthesis and SAR of analogues of the M1 allosteric agonist TBPB. Part I: Exploration of alternative benzyl and privileged structure moieties. Bioorg. Med. Chem. Lett. [Epub ahead of print]

Bridges TM, Lindsley CW. 2008. G-protein-coupled receptors: from classical modes of modulation to allosteric mechanisms. ACS Chem. Biol. 3: 530-541.

Jones CK, Brady AE, Davis AA, et al. 2008. Novel selective allosteric activator of the M1 muscarinic acetylcholine receptor regulates amyloid processing and produces antipsychotic-like activity in rats. J. Neurosci. 28: 10422-1033.

Miller NR, Daniels RN, Bridges TM, et al. 2008. Synthesis and SAR of analogs of the M1 allosteric agonist TBPB. Part II: Amides, sulfonamides and ureas—the effect of capping the distal basic piperidine nitrogen. Bioorg. Med. Chem. Lett. [Epub ahead of print]

Geneviève Oligny-Longpré

Audet M, Bouvier M. 2008. Insights into signaling from the β2-adrenergic receptor structure. Nat. Chem. Biol. 4: 397-403.

Azzi M, Charest PG, Angers S, et al. 2003. β-arrestin-mediated activation of MAPK by inverse agonists reveals distinct active conformations for G protein-coupled receptors. Proc. Natl. Acad. Sci. USA 100: 11406-11411. Full Text

Charest PG, Oligny-Longpré G, Bonin H, et al. 2007. The V2 vasopressin receptor stimulates ERK1/2 activity independently of heterotrimeric G protein signalling. Cell Signal. 19: 32-41.

Galandrin S, Bouvier M. 2006. Distinct signaling profiles of β1 and β2 adrenergic receptor ligands toward adenylyl cyclase and mitogen-activated protein kinase reveals the pluridimensionality of efficacy. Mol. Pharmacol. 70: 1575-1584. Full Text

Galandrin S, Oligny-Longpré G, Bonin H, et al. 2008. Conformational rearrangements and signaling cascades involved in ligand-biased mitogen-activated protein kinase signaling through the beta1-adrenergic receptor. Mol. Pharmacol. 74: 162-172.

Galandrin S, Oligny-Longpré G, Bouvier M. 2007. The evasive nature of drug efficacy: implications for drug discovery. Trends Pharmacol. Sci. 28: 423-430.

Jonathan Violin

Drake MT, Violin JD, Whalen EJ, et al. 2008. β-arrestin-biased agonism at the β2-adrenergic receptor. J. Biol. Chem. 283: 5669-5676.

Kim IM, Tilley DG, Chen J, et al. 2008. Beta-blockers alprenolol and carvedilol stimulate β-arrestin-mediated EGFR transactivation. Proc. Natl. Acad. Sci. USA 105: 14555-14560. Full Text

Shukla AK, Violin JD, Whalen EJ, et al. 2008. Distinct conformational changes in β-arrestin report biased agonism at seven-transmembrane receptors. Proc. Natl. Acad. Sci. USA 105: 9988-9993. Full Text

Violin JD, DiPilato LM, Yildirim N, et al. 2008. β2-adrenergic receptor signaling and desensitization elucidated by quantitative modeling of real time cAMP dynamics. J. Biol. Chem. 283: 2949-2961.

Violin JD, Lefkowitz RJ. 2007. β-arrestin-biased ligands at seven-transmembrane receptors. Trends Pharmacol. Sci. 28: 416-422.

Violin JD, Ren XR, Lefkowitz RJ. 2006. G-protein-coupled receptor kinase specificity for beta-arrestin recruitment to the β2-adrenergic receptor revealed by fluorescence resonance energy transfer. J. Biol. Chem. 281: 20577-20588. Full Text

Whalen EJ, Foster MW, Matsumoto A, et al. 2007. Regulation of beta-adrenergic receptor signaling by S-nitrosylation of G-protein-coupled receptor kinase 2. Cell 129: 511-522. Full Text

Wisler JW, DeWire SM, Whalen EJ, et al. 2007. A unique mechanism of beta-blocker action: carvedilol stimulates beta-arrestin signaling. Proc. Natl. Acad. Sci. USA 104: 16657-16662. Full Text

Lakshmi Devi

Décaillot FM, Rozenfeld R, Gupta A, Devi LA. 2008. Cell surface targeting of μ–δ opioid receptor heterodimers by RTP4. Proc. Natl. Acad. Sci. USA Oct 3. [Epub ahead of print] Full Text

Gomes I, Gupta A, Filipovska J, et al. 2004. A role for heterodimerization of mu and delta opiate receptors in enhancing morphine analgesia. Proc. Natl. Acad. Sci. USA 101: 5135-5139. Full Text

Gomes I, Jordan BA, Gupta A, et al. 2000. Heterodimerization of μ and δ opioid receptors: A role in opiate synergy. J. Neurosci. 20: RC110. Full Text

Jordan BA, Devi LA. 1999. G-protein-coupled receptor heterodimerization modulates receptor function. Nature 399: 697-700.

Rozenfeld R, Devi LA. 2007. Receptor heterodimerization leads to a switch in signaling: β-arrestin2-mediated ERK activation by μ–δ opioid receptor heterodimers. FASEB J. 21: 2455-2565. Full Text

Jonathan Javitch

Guo W, Urizar E, Kralikova M, et al. 2008. Dopamine D2 receptors form higher order oligomers at physiological expression levels. EMBO J. 27: 2293-2304.

Skrabanek L, Murcia M, Bouvier M, et al. 2007. Requirements and ontology for a G protein-coupled receptor oligomerization knowledge base. BMC Bioinformatics 8: 177. Full Text

Lee-Yuan Liu-Chen

Béguin C, Potter DN, Dinieri JA, et al. 2008. N-methylacetamide analog of salvinorin A: a highly potent and selective κ-opioid receptor agonist with oral efficacy. J. Pharmacol. Exp. Ther. 324: 188-195.

Chen C, Li JG, Chen Y, et al. 2006. GEC1 interacts with the κ opioid receptor and enhances expression of the receptor. J. Biol. Chem. 281: 7983-7993. Full Text

Chen Y, Chen C, Kotsikorou E, et al. 2008. GEC1-κ opioid receptor binding involves hydrophobic interactions: GEC1 has chaperone-like effect. J. Biol. Chem. Nov 11. [Epub ahead of print]

Chen Y, Chen C, Wang Y, Liu-Chen LY. 2006. Ligands regulate cell surface level of the human kappa opioid receptor by activation-induced down-regulation and pharmacological chaperone-mediated enhancement: differential effects of nonpeptide and peptide agonists. J. Pharmacol. Exp. Ther. 319: 765-775. Full Text

Li JG, Haines DS, Liu-Chen LY. 2008. Agonist-promoted Lys63-linked polyubiquitination of the human κ-opioid receptor is involved in receptor down-regulation. Mol. Pharmacol. 73: 1319-1330.

Li JG, Chen C, Liu-Chen LY. 2007. N-Glycosylation of the human κ opioid receptor enhances its stability but slows its trafficking along the biosynthesis pathway. Biochemistry 46: 10960-10970.

Wang Y, Dun SL, Huang P, et al. 2006. Distribution and ultrastructural localization of GEC1 in the rat CNS. Neuroscience 140: 1265-1276.

Ken Valenzano

Bernier V, Morello JP, Zarruk A, et al. 2006. Pharmacologic chaperones as a potential treatment for X-linked nephrogenic diabetes insipidus. J. Am. Soc. Nephrol. 17: 232-243. Erratum in: J. Am. Soc. Nephrol. 2006. 17: 591. dosage error in text. Full Text

Leandro P, Gomes CM. 2008. Protein misfolding in conformational disorders: rescue of folding defects and chemical chaperoning. Mini Rev. Med. Chem. 8: 901-911.


Craig Lindsley, PhD

Vanderbilt University Medical Center
e-mail | web site | publications

Craig Lindsley is an associate professor of pharmacology and chemistry at Vanderbilt University Medical Center. He received his PhD from the University of California, Santa Barbara and did his postdoctoral work at Harvard University. Prior to moving to Vanderbilt, he was at Merck & Co., where he led the Technology-Enabled Synthesis Group at the company's West Point, PA, facility.

Geneviève Oligny-Longpré

University of Montreal
e-mail | web site | publications

Geneviève Oligny-Longpré is a PhD student in the laboratory of Michel Bouvier at the University of Montreal.

Jonathan Violin, PhD

Trevena Inc.
Duke University Medical Center
e-mail | publications

Jonathan Violin is a research scientist and co-founder at Trevena, Inc. Prior to starting Trevena, Violin was a research associate at Duke University Medical Center in the laboratory of Robert J. Lefkowitz from 2003 to 2008. From 2006 to 2007 he was also an intern in the Office of Licensing and Ventures at Duke University.

Violin obtained his PhD from the University of California, San Diego in 2003 and his MBA in Health Sector Management from the Fuqua School of Business at Duke University in 2007.

Lakshmi Devi, PhD

Mount Sinai Medical Center
e-mail | web site | publications

Lakshmi Devi is a professor of pharmacology and systems therapeutics and a professor of psychiatry at Mount Sinai Medical Center. She is also the associate dean for academic enhancement and mentoring. Devi received her PhD from the University of Windsor and did her postdoctoral work at the Vollum Institute and the Addiction Research Foundation.

Jonathan A. Javitch, MD, PhD

Columbia University
e-mail | web site | publications

Jonathan Javitch is a professor of psychiatry and pharmacology in the Center for Recognition and in the Department of Physiology & Cellular Biophysics at Columbia University. He is director of the Division of Molecular Therapeutics and scientific director of the Lieber Center for Schizophrenia Research.

Javitch completed the joint MD–PhD program at the Johns Hopkins University School of Medicine where he was a graduate student in Solomon Snyder's lab. After graduating from Hopkins, Javitch completed a medical internship and psychiatric residency at the Columbia Presbyterian Hospital and the New York State Psychiatric Institute. He did postdoctoral work on the structure of dopamine receptors with Arthur Karlin at Columbia University.

Lee-Yuan Liu-Chen, PhD

Temple University
e-mail | web site | publications

Lee-Yuan Liu-Chen is a professor of pharmacology at Temple University. She received her PhD from the Massachusetts Institute of Technology and was a postdoctoral fellow at Massachusetts General Hospital and Harvard Medical School.

Ken Valenzano, PhD

Amicus Therapeutics
e-mail | web site | publications

Ken Valenzano is senior director of pharmacology at Amicus Therapeutics. Prior to moving to Amicus he was a group leader at Purdue Pharma and a research scientist at Pharmacopeia.

Catherine Zandonella

Catherine Zandonella is a science writer based in New York City, covering such topics as environmental science, public health, and applied technology. She has a master's degree in public health from the University of California, Berkeley. Zandonella has written for a number of publications, including New Scientist, The Scientist, and Nature.