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  • Twenty Questions
  • Published:

The state of GPCR research in 2004

Nature Reviews Drug Discovery volume 3, pages 577–626 (2004)Cite this article

Key Points

List of questions

  1. 1

    What new technologies are having the greatest impact on GPCR research, and why?

  2. 2

    What tools and technologies for GPCR research would you most like to be available in the future, and why?

  3. 3

    What are the main pitfalls and advantages of currently used cell-based assay systems for GPCRs?

  4. 4

    How will changing views of agonist and antagonist behaviour at GPCRs change the way we view these receptors as therapeutic targets?

  5. 5

    Many predictions for heptahelical receptors have been based on using the rhodopsin crystal structure as a template. How successful have these been?

  6. 6

    How close are we to having further GPCR structures, and what are the main barriers to obtaining these?

  7. 7

    What big questions remain for GPCRs at the structure/function interface?

  8. 8

    How widespread do you think GPCR heteromerization will turn out to be, and how great a functional significance will it have?

  9. 9

    Almost two-thirds of drugs on the market are thought to interact with GPCRs, by far the largest family of targets, and yet new drugs targeting GPCRs are few and far between. Why?

  10. 10

    What are the barriers to achieving specificity using GPCR ligands?

  11. 11

    How will our increasing knowledge of interacting protein partners for GPCRs change the way that we think about achieving selective GPCR modulation?

  12. 12

    Could there be an approach to GPCR pharmacology based around monoclonal antibodies or proteins, rather than small molecules?

  13. 13

    How close are we to being able to integrate understanding of how individual GPCRs function with their role in disease states?

  14. 14

    How successful are the animal models that seek to recapitulate diseases linked to the aberrant function of peptide-activated GPCRs?

  15. 15

    In your opinion, which diseases are most strongly associated with aberrant function of peptide-activated GPCRs?

  16. 16

    What are the main hurdles that will need to be overcome to create further successful therapeutic approaches based around targeting GPCRs?

  17. 17

    What would you describe as the major concerns surrounding the continued development of GPCR-targeted therapies?

  18. 18

    What effect is the deorphanizing of GPCRs likely to have on the field?

  19. 19

    What outstanding questions in GPCR research are likely to be clarified in the next few years?

  20. 20

    What areas are unlikely to be clarified by research over the next few years?

Abstract

G-protein-coupled receptors (GPCRs) comprise the largest single class of cell-surface receptors, and have a history of being excellent therapeutic targets for a number of diseases. Yet several fundamental questions remain regarding their underlying biology, and many GPCRs that could be promising targets for drug discovery are still uncharacterized at the level of identified ligand or biological function. In an attempt to find some answers, we posed 20 questions of fundamental importance to the future development of the field to 20 of the world's leading experts on GPCR research, and here we present their replies.

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Figure 1: Use of RET to assess GPCR oligomerizaton.
Figure 2: High-throughput screening based on second-messenger production has enabled the discovery of several GPCR antagonists.
Figure 3: GPCR–Gα fusion proteins as a model system for the analysis of receptor–G-protein coupling.
Figure 4: The crystal structure of rhodopsin.
Figure 5: Proposed roles for GPCR heterodimerization.
Figure 6: Use of orphan receptors to discover novel transmitters.

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Acknowledgements

Nature Reviews Drug Discovery would like to thank all the participants who contributed to the questionnaire. We also wish to acknowledge J. Bockaert, M. Bouvier, A. Christopoulos, S. R. George, B. Nürnberg, R. Seifert and R. E. Stenkamp for their invaluable help in preparing the figures.

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B.P.R. is Scientific Director of the start-up company PharmaLeads.

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 Tamas Bartfai Director and Professor of Neuropharmacology, Harold L. Dorris Neurological Research Center, The Scripps Research Institute, La Jolla, San Diego, USA http://dorriscenter.scripps.edu/bartfai.html Jeffrey L. Benovic Professor and Vice Chair of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA http://www.kcc.tju.edu/Staff/StaffDefault.asp/ Joël Bockaert Professor of Neuroscience, Laboratoire de Génomique Fonctionelle, Department of Neurobiology, Centre Nationale de la Recherche Scientifique — UPR2580, Montpellier, France http://www.montp.inserm.fr/ifr3/upr2580/ Richard A. Bond Associate Professor of Pharmacology, Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Texas, USA http://www.uh.edu/pps/ppsp/fapages/fpc/bond.htm Michel Bouvier Professor and Chairman, Department of Biochemistry, Université de Montréal, Quebec, Canada http://www.mapageweb.umontreal.ca/bouvier/ Arthur Christopoulos NHMRC Senior Research Fellow and Head, Molecular Pharmacology Laboratory, Department of Pharmacology, University of Melbourne, Parkville , Victoria , Australia http://www.pharmacology.unimelb.edu.au/research/molpharm.html Olivier Civelli Professor of Pharmacology, Department of Pharmacology, University of California , Irvine , California , USA http://www.ucihs.uci.edu/pharmaco/Faculty/Civelli.html Lakshmi A. Devi  Professor of Pharmacology and Biological Chemistry, Mount Sinai School of Medicine , New York , New York , USA http://www.mssm.edu/labs/devi/ Susan R. George Professor of Medicine and Pharmacology, Canada Research Chair in Molecular Neuroscience, Department of Pharmacology, University of Toronto , Toronto , Canada http://www.utoronto.ca/grdpharm/george.htm Akio Inui Associate Professor of Clinical Molecular Medicine, Division of Diabetes, Digestive and Kidney Diseases, Department of Clinical Molecular Medicine, Kobe University Graduate School of Medicine , Chuo-ku Kobe , Japan http://www.med.kobe-u.ac.jp/WelcomeE.html Brian Kobilka Professor of Molecular and Cellular Physiology and Medicine, Stanford University School of Medicine , Stanford , California , USA http://www.med.stanford.edu/kobilkalab/index.html Rob Leurs  Professor of Medicinal Chemistry, Leiden/Amsterdam Center for Drug Research, Vrije Universiteit, Faculty of Science, Medicinal Chemistry , Amsterdam , the Netherlands http://www.chem.vu.nl/far/Medchem/staff.html Rick Neubig Professor of Pharmacology and Associate Professor of Internal Medicine, Department of Pharmacology, University of Michigan Medical School , Ann Arbor , Michigan , USA http://sitemaker.umich.edu/neubig.lab Jean-Philippe Pin CNRS Research Director and Head of the Molecular Pharmacology Department, Departement de Pharmacologie Moleculaire, Laboratoire de Génomique Fonctionnelle, Centre Nationale de la Researche Scientifique , Montpellier , France http://www.montp.inserm.fr/ifr3/upr2580/jppin/Index.htm Rémi Quirion Professor of Psychiatry and Scientific Director, Institute of Neurosciences, Mental Health and Addiction, Canadian Institutes of Health Research, Montreal , Quebec , Canada http://www.douglas.mcgill.ca/quirionlab Bernard P. Roques Professor (emeritus), Université René Descartes , Paris , France http://www.pharmacie.univ-paris5.fr/chimie1.htm Thomas P. Sakmar Richard M. and Isabel P. Furlaud Professor, Laboratory of Molecular Biology and Biochemistry, The Rockefeller University , New York , New York , USA http://www.rockefeller.edu/labheads/sakmar/sakmar-lab.html Roland Seifert Associate Professor for Pharmacology and Toxicology, Department of Pharmacology and Toxicology, The University of Kansas , Lawrence , Kansas , USA http://people.ku.edu/~rseifert/Html/SEIFERTLABPAGE.html Ronald E. Stenkamp Professor, Departments of Biological Structure and Biochemistry, University of Washington , Seattle , Washington , USA http://faculty.washington.edu/stenkamp/  Philip G. Strange  Professor of Neuroscience, School of Animal and Microbial Sciences, University of Reading, Whiteknights , Reading , UK http://www.ams.rdg.ac.uk/DMCB/neurosci/

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DATABASES

Entrez Gene

5-HT2A receptor

α1-adrenoceptor

α2-adrenoceptor

β1-adrenoceptor

β2-adrenoceptor

ACE

adenosine A1 receptor

AgRP

apelin

CALCR

cannabinoid CB1 receptor

CCK1 receptor

CCK2 receptor

CCR5

CRLR

CXCR4

dopamine D1 receptor

dopamine D2 receptor

FSHR

GABAA receptor

GABAB receptor

GAIP

GALR1

GALR2

ghrelin

glucagon-like peptide-1

hERG

histamine H1 receptor

histamine H2 receptor

histamine H3 receptor

HM74

JAK

KISS1

LHR

MAPK

MC4R

mGlu1 receptor

mGlu2 receptor

mGlu3 receptor

muscarinic M1 receptor

muscarinic M2 receptor

neuropeptide Y5 receptor

NK1 receptor

NMDA receptor

NSF

NTSR1

PTH

PTHR

RAMPs

RGS4

rhodopsin

thyrotropin receptor

vasopressin V1A receptor

vasopressin V2 receptor

Online Mendelian Inheritance in Man

Hirschsprung's disease

hypogonadotropic hypogonadism

irritable bowel syndrome

multiple sclerosis

rheumatoid arthritis

schizophrenia

FURTHER INFORMATION

GPCR database

Glossary

ANORECTIC

Suppressing or causing loss of appetite.

ATOMIC FORCE MICROSCOPE

(AFM.) A microscope that nondestructively measures the forces (at the atomic level) between a sharp probing tip (which is attached to a cantilever spring) and a sample surface. The microscope images structures at the resolution of individual atoms.

CHROMOPHORE

A light-absorbing molecule, such as pterin or retinal. Often physically associated with a protein partner to form a photoreceptor/phototransducer.

DESENSITIZATION

The mechanism by which a ligand becomes less effective on a receptor during a prolonged application.

DIPSOGENIC

Something that induces a strong need or desire to drink fluids; thirst-inducing.

FEAR CONDITIONING

A test to measure the ability of a rodent to learn and remember an association between an aversive experience and environmental cues. Learning and memory are assessed by scoring freezing behaviour in the presence of the cue or context.

FLUORESCENCE CORRELATION SPECTROSCOPY

(FCS.) A single-molecule technique that examines the diffusion of fluorescent molecules across a small confocal volume. It can be used to examine ligand binding based on the different diffusion speeds of a fluorescent molecule, when free and bound to a receptor.

FLUOROPHORE

A small molecule or a part of a larger molecule that can be excited by light to emit fluorescence.

FLUOROMETRIC IMAGING PLATE READER

A high-throughput screening device used to quantify real-time intracellular calcium fluctuations simultaneously in multi-well plates. In this cell-based assay, cells are loaded with a dye that can be excited once bound to calcium. Various GPCRs can be coupled to calcium pathways using G-protein chimeras or promiscuous coupling to Gα15/Gα16.

FLUORESCENCE LIFETIME IMAGING

An imaging technique that takes advantage of the change in the life-time of fluorescence of an energy donor when fluorescence resonance energy transfer occurs.

G PROTEIN

A heterotrimeric GTP-binding and -hydrolysing protein that interacts with cell-surface receptors, often stimulating or inhibiting the activity of a downstream enzyme. G proteins consist of three subunits: the α-subunit, which contains the guanine-nucleotide-binding site; and the β- and γ-subunits, which function as a heterodimer.

GREEN FLUORESCENT PROTEIN

An autofluorescent protein, originally isolated from the jellyfish Aequorea victoria, that can be genetically conjugated with proteins to make them fluorescent.

GTPγS

A hydrolysis-resistant analogue of GTP that binds to G proteins with high affinity. [35S]GTPγS is frequently used to monitor GPCR-mediated guanine nucleotide exchange at G proteins.

INOTROPIC

Affecting the contraction of muscle, especially heart muscle.

INTERNAL FLUORESCENCE REFLECTION

An imaging technique that allows the detection of single-molecule fluorescence signals.

IONOTROPIC RECEPTOR

A term that describes a receptor that exerts its effects through the modulation of ion-channel activity. This term is now commonly used for receptors with intrinsic ion channels.

OCCAM'S RAZOR

A principle of 'postulate parsimony', articulated by William of Occam in the thirteenth century, which suggests that all else being equal, simpler explanations should be preferred over more complex ones.

ONTOGENY

In this context, the production and formation (in terms of adoption of three-dimensional structure) of receptor proteins.

ORPHAN RECEPTOR

A receptor for which no endogenous ligand has been identified.

PALMITOYLATION

A post-translational modification in which palmitic acid, a fatty carbon chain, is attached to a cysteine residue by a thio-ester bond.

PDZ BINDING MOTIF

Protein–protein interaction domain that often occurs in scaffolding proteins and is named after the founding members of this protein family (PSD-95, DLG and ZO-1).

PHARMACOPHORE

The ensemble of steric and electronic features that is necessary to ensure optimal interactions with a specific biological target structure and to trigger (or to block) its biological response.

PHASIC

Physiological events that occur only transiently with intervening periods of inactivity.

POSITRON EMISSION TOMOGRAPHY

A radioisotope method for localizing chemicals, such as receptor-bound ligands, in vivo.

PROTEAN LIGAND

A ligand that acts as an agonist on one specific pathway, and as an inverse agonist on another pathway.

PROTOMERS

Identical subunits in an oligomeric protein complex.

QUANTUM DOTS

Nanometre-scale particles of semiconductor materials. Optically, quantum dots are similar to fluorophores in that they absorb light at one wavelength (colour) and emit light at another. They could potentially replace fluorophores in many bioassays, as their emission efficiency does not fade over time as occurs with regular fluorophores. Similar to fluorophores, they can also be conjugated to biomolecules.

QT INTERVAL

On an electrocardiogram, the QT interval represents the time between the electrical activation and inactivation of the ventricles, the lower chambers of the heart.

REVERSE PHARMACOLOGY

The process that leads from an orphan receptor to the identification of its endogenous ligand.

SECRETED ALKALINE PHOSPHATASE (SEAP) ASSAY

A gene-reporter assay in which transcription of a thermostable secreted alkaline phosphatase is induced by the accumulation of an intracellular second messenger. The SEAP is quantitatively secreted in the supernatant, which simplifies the detection step of this assay.

SINGLE-MOLECULE FORCE EXTENSION

A measurement of mechanical properties between single molecules using atomic force microscopy.

SMOOTHENED RECEPTORS

Receptors involved in development first identified using Drosophila genetics. These receptors are constitutively active in the absence of their associated protein Patch, the receptor for Hedgehog. Hedgehog is supposed to prevent Patch from inhibiting constitutive activity of Smoothened, leading to Smoothened activation.

TOLERANCE

Reduced drug responsiveness with repeated exposure to a constant drug dose.

TONIC

Physiological events that occur in a sustained manner.

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Ellis, C., The Nature Reviews Drug Discovery GPCR Questionnaire Participants.. The state of GPCR research in 2004 . Nat Rev Drug Discov 3, 577–626 (2004). https://doi.org/10.1038/nrd1458

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